Imidazolonylquinolines and the use thereof as ATM kinase inhibitors

ABSTRACT

These imidazolonylquinoline compounds are useful in the inhibition, regulation and/or modulation of signal transduction by kinases, in particular ATM kinase, furthermore in pharmaceutical compositions, and in their use for the treatment of diseases which relate to ATM kinase, in particular cancer.

BACKGROUND OF THE INVENTION

The present invention relates to specific imidazolonylquinolinecompounds and to the use thereof in the inhibition, regulation and/ormodulation of signal transduction by kinases, in particular ATM kinase,furthermore to pharmaceutical compositions which comprise thesecompounds, and to the use of the compounds for the treatment of diseaseswhich relate to ATM kinase, in particular cancer.

The serine/threonine protein kinase ATM (ataxia telangiectasia mutatedkinase) belongs to the PIKK family of kinases having catalytic domainswhich are homologous with phospho-inositide-3 kinases (PI3 kinase,PI3K). These kinases are involved in a multiplicity of key cellularfunctions, such as cell growth, cell proliferation, migration,differentiation, survival and cell adhesion. In particular, thesekinases react to DNA damage by activation of the cell cycle arrest andDNA repair programmes (DDR: DNA damage response). ATM is a product ofthe ATM gene and plays a key role in the repair of damage to the DNAdouble strand (DSB. double strand breaks) by homologous recombinationand non-homologous end-to-end joining (NHEJ). Double-strand damage ofthis type is particularly cytotoxic.

One of the constant features of tumours in humans is their genomicinstability, where the specific defects of the DNA repair mechanism inmost types of cancer are unknown to date. This instability representsthe therapeutic starting point for chemotherapy, which has beenpredominantly practised for some time. In addition, there are a fewsyndromes in which the basic genetic influencing factor can beattributed to mutation, accompanied by a loss of function, of a genewhich modulates the reaction to damage to the DNA double strand. Thisincludes ataxia telangiectasia, which is caused by a defective ATM gene.A common feature of all these syndromes is that they cause extremeradiation sensitivity (Lavin & Shiloh (1997) Annu. Rev. Immunol. 15:177; Rotman & Shiloh (1998) Hum. Mol. Genet. 7: 1555, incorporated intheir totality herein by way of reference). ATM-defective cells arecorrespondingly sensitive to agents and measures which cause damage tothe DNA double strand, which makes ATM an attractive target for chemo-and radiosensitisation in cancer treatment.

Although the molecules caffeine and wortmannin which were initiallyinvestigated against this background exhibited radiosensitisation,attributed, inter alia, to inhibition of ATM, they are, however, tootoxic in vivo for possible therapeutic use. Staring from the chemicalstructure of the PI3K inhibitor LY294002, KuDOS Pharmaceuticalsdeveloped the first potent and selective ATM inhibitor: KU-55933(2-morpholino-6-(thianthren-1-yl)-4H-pyran-4-one). This facilitatedsensitisation to ionising radiation and DNA double strand-damagingchemotherapeutic agents (Hickson, I., et al. (2004). Cancer Res 64,9152-9159, incorporated in its totality herein by way of reference).However, KU-55933 proved to be unsuitable for in vivo use, presumablyowing to its high lipophilicity. Based on KU-55933, KU-60019(2-((2S,6R)-2,6-dimethylmorpholino)-N-(5-(6-morpholino-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide)and KU-559403(2-(4-methylpiperazin-1-yl)-N-[5-(6-morpholino-4-oxopyran-2-yl)thioxanthen-2-yl]acetamide)were developed with slight modification of the basic structure, enablingsolubility and potency to be improved. In the meantime, it has beenreported, for example, that it has been possible to sensitiseglioblastoma-initiating cells for irradiation safely and effectively byKU-60019, from which it was concluded that KU-60019 is able to functionfor radiation sensitisation of a whole series of brain tumours (VecchioD. et al. (2015), Int. J. Cancer 136: 1445, incorporated in its totalityherein by way of reference).

The provision of small molecules which effectively inhibit, regulateand/or modulate signal transduction by kinases, in particular ATMkinase, is desirable and an object of the present invention.

It is furthermore desirable that kinase inhibitors of this type areselective, i.e. have no or significantly lower activity against otherkinases. Thus, off-target effects or associated toxicities can bereduced.

DESCRIPTION OF THE INVENTION

The object has surprisingly been achieved by compounds of the formula(I)

where

-   R1 denotes A,-   R3 denotes A or H,-   A in each case independently denotes unbranched or branched alkyl    having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, where, independently    of one another, 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced by    Hal,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted, independently of one    another, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY, -Het² and/or    —SO₂—Het²,-   Het² denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6    or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or monosubstituted by A,-   HET denotes a 5- or 6-membered aromatic heterocycle having 1, 2 or 3    N atoms and optionally an O atom or S atom, where this heterocycle    is linked to the N atom of the skeleton via a ring C atom and where    this heterocycle may be unsubstituted or substituted by one, two or    three substituents, which are selected, independently of one    another, from the group consisting of: Hal, A, Het², CN,    —(CY₂)_(p)—OY, —(CY₂)_(p)—OZ, —(CY₂)_(p)—O-Het²,    —(CY₂)_(p)—O—(CY₂)_(t)-Het², —(CY₂)_(p)—O—(CY₂)_(t)—NYY,    —(CY₂)_(p)—O—(CY₂)_(t)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—POAA,    —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY,    —(CY₂)_(p)—NY—COY, —SO₂—Het², CyA, —(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y,    —(CY₂)_(p)—NY—SO₂—Y, and —(CY₂)_(p)—SO₂—Y, and where this    heterocycle may be part of a bicyclic 11- or 12-membered aromatic    heterocycle, where this bicyclic aromatic heterocycle may overall be    unsubstituted or substituted by one, two, three or more    substituents, which are selected, independently of one another, from    the group consisting of: Hal, A, Het², —ON, —(CY₂)_(p)—OY,    —(CY₂)_(p)—OZ, —(CY₂)_(p)—O-Het², —(CY₂)_(p)—O—(CY₂)_(t)-Het²,    —(CY₂)_(p)—O—(CY₂)_(t)—NYY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,    —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY, —SO₂—Het², CyA,    —(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y, —(CY₂)_(p)—NY—SO₂—Y, and    —(CY₂)_(p)—SO₂—Y,-   Y denotes H or A,-   Z denotes unbranched or branched alkenyl having 2, 3, 4, 5, 6, 7, 8,    9 or 10 C atoms, where, independently of one another, 1, 2, 3, 4, 5,    6 or 7 H atoms may be replaced by Hal,-   CyA denotes cycloalkyl having 3, 4, 5, 6, 7 or 8 ring C atoms which    is unsubstituted or mono- or polysubstituted, independently of one    another, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY and/or —(CY₂)_(p)—NY—COY,-   Hal denotes F, Cl, Br or I, and-   p denotes 0, 1, 2, 3, 4, 5 or 6-   t denotes 1, 2, 3, 4, 5 or 6,    and/or pharmaceutically usable derivative, salt, solvate, tautomer,    stereoisomer thereof, including mixtures thereof in all ratios.

As stated in greater detail below, the compounds are to be understood insuch a way that the atoms, such as, for example, H, C, N, in each casealso include the heavier isotopes of these atoms. This applies, inparticular, to H, where deuterium can advantageously be employed, asshown by the examples.

Compounds according to the invention have surprisingly proven to bepotent inhibitors of ATM kinase. Even more surprising is the selectivityfor other related kinases, such as, for example, mTOR (mammalian targetof rapamycin) kinase, a further protein kinase from the PIK kinasefamily (also known as class IV PI3K).

In total contrast to the present invention, international patentapplication WO 2010/139731 discloses that the imidazolonylquinolinecompounds described and claimed there are preferably inhibitors of classI PI3 kinases and/or mTOR kinase. Class I PI3 kinases are lipid kinases.Correspondingly, experimental data show IC₅₀ values for mTOR in therange down to less than 3 nM, i.e. very strong inhibition.

The compounds according to the invention again impressively confirm howstructural differences that at first sight appear relatively small exerta crucial influence on the biological activity.

In addition, the compounds according to the invention are alsodistinguished by the absence of the frequently observed, undesiredinhibition of cardiac ion channels, in particular of Kv1.11 hERG,blockage of which may result in life-threatening arrhythmia.

The compounds according to the invention thus open up completely newpossibilities in cancer therapy, for example as monotherapy in the caseof tumours having defective DNA double-strand repair ability or incombination with radio- or chemotherapy, in particular as radio- andchemosensitisers in the treatment of cancer, particularly preferably asradiosensitisers.

The compounds of the formula (I) can therefore be used for theinhibition of cancer and for the sensitisation of cancer cells toanti-cancer agents and/or ionising radiation. The invention also relatesto the use of the compounds of the formula (I) in the treatment ofcancer, tumours and/or metastases, in combination with radiotherapyand/or an anti-cancer agent, preferably radiotherapy.

Above and below, the radicals R1, R3, Y, A, Z, CyA, Het¹, Het², HET andHal as well as p and t have the meanings indicated above in the case ofthe formula (I), unless expressly indicated otherwise. In the case ofthe multiple occurrence of individual residues within a compound orradical, the residues adopt, independently of one another, the meaningsindicated, unless expressly indicated otherwise. For example, theresidues YY in the radical —NYY, in which they may occur multiple times,are identical or different, but are preferably in each case selected,independently of one another, from the meanings indicated above and/orbelow (for example methyl and/or ethyl), unless expressly indicatedotherwise. In the case of the multiple occurrence of Y, the radical mayalternatively also be denoted by Y′, Y″, Y″′ and Y″″. A correspondingsituation applies to the other residues or number variables.Correspondingly, the formulation “cycloalkyl which is unsubstituted ormono- or polysubstituted, independently of one another, by Hal, A, . . .and/or —(CY₂)_(p)—NY—COY” means that the cycloalkyl radical may bemonosubstituted by one of the said substituents, or may have a pluralityof substituents, which are selected, independently of one another, fromthe said substituents, in the case of cycloalkyl Hal, A, CN,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY and/or—(CY₂)_(p)—NY—COY, i.e., for example, a cyclohexyl having the threesubstituents fluorine, chlorine and —CH₂—NH₂.

The terms used here for the definition of the compounds are generallybased on the rules of the IUPAC organisation for chemical compounds andin particular organic compounds. The terms for the explanation of theabove-mentioned compounds of the invention always have the followingmeanings, unless indicated otherwise in the description or claims.

The term “unsubstituted” means that a radical, a group or a residuecarries no substituents. The term “substituted” means that a radical, agroup or a residue carries one or more substituents. If only“substituted” is mentioned below with respect to a certain group or acertain radical whose substitution is defined specifically in connectionwith the above formula (I), it goes without saying that thissubstitution corresponds to that mentioned above, unless specificallyindicated otherwise. It also goes without saying here in the sense ofthe invention that a radical can adopt all meanings mentioned previouslyin the description for the corresponding radical through reference to“the above-mentioned meaning” without specification thereof in greaterdetail.

“A” stands for an unbranched or branched alkyl having 1, 2, 3, 4, 5, 6,7, 8, 9 or 10 C atoms, where, independently of one another, 1, 2, 3, 4,5, 6 or 7 H atoms may be replaced by Hal. “A” is particularly preferablyunbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, where,independently of one another, 1, 2, 3, 4 or 5 H atoms may be replaced byHal, i.e. F, Cl, Br and/or I. It goes without saying that Hal in thisconnection can stand for various halogens F, Cl, Br, I, i.e., forexample, 1 H may be replaced by F, another H may be replaced by Cl. Veryparticular preference is given to C₁₋₄-alkyl, where, independently ofone another, 1, 2 or 3 H atoms may be replaced by Hal. A C₁₋₄-alkyl ofthis type is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl,most preferably methyl, ethyl, fluoromethyl, difluoromethyl ortrifluoromethyl. It goes without saying that the respective meanings of“A” are independent of one another in the radicals of a formulaaccording to the invention.

“Alkyl” herein denotes a saturated hydrocarbon radical, which isunbranched (linear) or branched and preferably has 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 C atoms, i.e. C₁₋₁₀-alkyl. Examples of alkyl radicals aremethyl, ethyl, propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-, 2-, 3- or4-methylpentyl, hexyl.

“Z” herein denotes unbranched or branched alkenyl having 2, 3, 4, 5, 6,7, 8, 9 or 10 C atoms, where, independently of one another, 1, 2, 3, 4,5, 6 or 7 H atoms may be replaced by Hal. Alkenyls have at least one C═Cdouble bond, may, in particular, also have two double bonds (dienes).Examples of suitable alkenyls are vinyl, allyl, propenyl —(CH₂CH═CH₂;—CH═CH—CH₃; —C(═CH₂)—CH₃), 1-, 2- or 3-butenyl, isobutenyl, 2-methyl-1-or 2-butenyl, 3-methyl-1-butenyl, 1,3-butadienyl,2-methyl-1,3-butadienyl, 2,3-dimethyl-1,3-butadienyl, 1-, 2-, 3- or4-pentenyl and hexenyl, particularly preferably allyl.

The term “CyA” herein denotes cycloalkyl, in particular cyclic alkylhaving 3, 4, 5 6, 7 or 8 ring C atoms, i.e. C₃₋₆-cycloalkyl which may beunsubstituted or mono- or polysubstituted, for example di- ortrisubstituted, independently of one another, by Hal, A, CN,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY and/or—(CY₂)_(p)—NY—COY. Examples of unsubstituted cycloalkyls arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Unsubstituted cyycloalkyl groups are preferred herein, inparticular cyclopropyl.

“Het¹” herein denotes a mono- or bicyclic aromatic heterocycle, i.e.hetaryl or heteroaryl, having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2,3 or 4 N, O and/or S atoms, i.e. at least one heteroatom, which may beunsubstituted or mono-, di- or trisubstituted, independently of oneanother, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,—(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY, -Het² and/or —SO₂—Het²

“Het¹” thus denotes a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15,preferably 5-10-membered mono- or bicyclic aromatic hydrocarbon radicalwhich includes at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms,in particular nitrogen, oxygen and/or sulfur, where the heteroatoms maybe identical different. The number of nitrogen atoms is preferably 0, 1,2, 3 or 4, and the number of oxygen and sulfur atoms is, independentlyof one another, 0 or 1, where at least one heteroatom must be present.Heterocycles containing nitrogen atoms are preferred. “Het¹” can beselected, irrespective of further substitutions, from, for example:furyl, in particular 2- or 3-furyl, thienyl, in particular 2- or3-thienyl, pyrrolyl, in particular 1-, 2- or 3-pyrrolyl, imidazolyl, inparticular 1-, 2-, 4- or 5-imidazolyl, pyrazolyl, in particular 1-, 3-,4- or 5-pyrazolyl, oxazolyl, in particular 2-, 4- or 5-oxazolyl,isoxazolyl, in particular 3-, 4- or 5-isoxazolyl, thiazolyl, inparticular 2-, 4- or 5-thiazolyl, isothiazolyl, in particular 3-, 4- or5-isothiazolyl, pyridyl, in particular 2-, 3- or 4-pyridyl, wherepyridyl and pyridinyl are used synonymously herein, pyrimidinyl, inparticular 2-, 4-, 5- or 6-pyrimidinyl, triazolyl, in particular1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl,triazinyl, tetrazolyl, in particular 1- or 5-tetrazolyl, oxadiazolyl, inparticular 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,thiadiazolyl, in particular 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, pyridazinyl,in particular 3- or 4-pyridazinyl, pyrazinyl, indolyl, in particular 1-,2-, 3-, 4-, 5-, 6- or 7-indolyl, isoindolyl, in particular 4- or5-isoindolyl, benzimidazolyl, in particular 1-, 2-, 4- or5-benzimidazolyl, indazolyl, in particular 1-, 2-, 3-, 4-, 5-, 6- or7-indazolyl, benzopyrazolyl, in particular 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, benzoxyazolyl, in particular 2-, 4-, 5-, 6- or7-benzoxazolyl, benzisoxazolyl, in particular 3-, 4-, 5-, 6-, or7-benzisoxazolyl, benzothiazolyl, in particular 2-, 4-, 5-, 6- or7-benzothiazolyl, benzisothiazolyl, in particular 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, quinolyl, inparticular 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, isoquinolyl, inparticular 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, cinnolinyl, inparticular 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, quinazolinyl, inparticular 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, quinoxalinyl, inparticular 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo[1,4]-oxazinyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl,phthalazinyl, indolizinyl, and pteridinyl. The linking “−” Het¹ can takeplace via any ring member of the heteroaryl group, so long as it appearschemically appropriate, where bonding via a C atom is preferred. If onlyone of the two rings in a bicyclic aromatic heterocycle (annelatedrings) contains one or more heteroatoms, the linking preferably takesplace via the ring which contains the heteroatom(s). One ring containsno heteroatom if none of the atoms forming the ring is a heteroatom,including atoms which are to be assigned to both rings. Particularlypreferred embodiments of Het1 are mentioned below.

“Het²” herein is a monocyclic saturated heterocycle having 2, 3, 4, 5, 6or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may beunsubstituted or monosubstituted by A. “Het²” preferably denotes amonocyclic saturated heterocycle having 3, 4 or 5 C atoms and 1 or 2 Nand/or O atoms. Examples of Het² are aziridinyl, oxiranyl, thiaranyl,azetidinyl, oxetanyl, dioxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuranyl, dithiolanyl, oxazolidinyl, piperidinyl,tetrahydropyranyl, piperazinyl, dioxanyl, thiomorpholinyl, morpholinyl,oxepanyl, thiepanyl, and azepanyl. N-containing monocyclic saturatedheterocycles are preferred, for example, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, where these may in accordancewith the general definition be unsubstituted or monosubstituted by A.Unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl count amongst preferred embodiments, particularly preferablyazetidinyl and piperazinyl. Furthermore, tetrahydropyranyl is alsopreferred. The linking “−” Het² in the group —SO₂—Het² typically takesplace via a C atom. Otherwise, i.e., for example, as a substituent ofHET, the linking can take place via any ring member of the heterocyclegroup, so long as it appears chemically appropriate, where here toobonding via a C atom is preferred.

For the purposes of the present invention, “HET” stands for a 5- or6-membered aromatic heterocycle having 1, 2 or 3 N atoms and optionallyan O atom or S atom, where this heterocycle is linked to the N atom ofthe skeleton via a ring C atom and where this heterocycle may beunsubstituted or substituted by one, two or three substituents, whichare selected, independently of one another, from the group consistingof: Hal, A, Het², CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—OZ, —(CY₂)_(p)—O-Het²,—(CY₂)_(p)—O—(CY₂)_(t)-Het², —(CY₂)_(p)—O—(CY₂)_(t)—NYY,—(CY₂)_(p)—O—(CY₂)_(t)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY,—(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY, —SO₂—Het², CyA,—(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y, —(CY₂)_(p)—NY—SO₂—Y, and —(CY₂)_(p)—SO₂—Y,and where this heterocycle may be part of a bicyclic 11- or 12-memberedaromatic heterocycle, where this bicyclic aromatic heterocycle mayoverall be unsubstituted or substituted by one, two, three or moresubstituents, which are selected, independently of one another, from thegroup consisting of: Hal, A, Het², —CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—OZ,—(CY₂)_(p)—O-Het², —(CY₂)_(p)—O—(CY₂)_(t)-Het²,—(CY₂)_(p)—O—(CY₂)_(t)—NYY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,—(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,—(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY, —SO₂—Het², CyA,—(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y, —(CY₂)_(p)—NY—SO₂—Y, and —(CY₂)_(p)—SO₂—Y.In other words, the second ring of the bicyclic aromatic heterocycle mayalso be correspondingly substituted. In a first embodiment, “HET” isthus a monocyclic 5- or 6-membered aromatic heterocycle, in a secondembodiment is a bicyclic 11- or 12-membered aromatic heterocycle, whereit should be understood that the linking to the imidazolonylquinolineskeleton takes place via the ring of the bicyclic heterocycle thatcorresponds to the monocyclic HET. Specifically, this means that, in thecase of, for example, benzannelated systems, the linking takes place viathe ring that contains the heteroatom(s), so long as the heteroatom(s)are to be assigned to only one ring (and are not involved in the linkingto the second ring). In the bicyclic 11- or 12-membered aromaticheterocycle, both rings are aromatic. The fact that the bicyclicheterocycle may overall be substituted by one, two, three or moresubstituents is thus tantamount to these substituents being able to bepositioned overall at any desired point of the heterocycle (i.e. asdesired on any one of the ring parts).

The term “Hal”, or also “halogen”, “halogen atom”, “halogensubstituent”, herein denotes one or more atoms of fluorine (F), bromine(Br), chlorine (Cl) or iodine (I). The terms “dihalogen”, “trihalogen”and “perhalogen” relate to two, three or four substituents, where eachsubstituent can be selected, independently of one another, from thegroup of F, Cl, Br or I. “Halogen” preferably means F, Cl or Br. F andCl are particularly preferred, in particular if the halogens aresubstituents on an alkyl (haloalkyl) or alkoxy group (for example CF₃and CF₃O).

“CN” can stand both for cyano and also for isocyano, where the meaningcyano (—CN) is preferred.

—POAA, —COOY, —CO—NYY, —COOY and —NY—COY are conventional notations forthe following groups:

The index p preferably denotes 0, 1, 2 or 3, particularly preferably 0.

The index t preferably denotes 1, 2, 3 or 4, particularly preferably 2.

Examples of —(CY₂)_(p)—OY, —(CY₂)_(p)—OZ, —(CY₂)_(p)—O-Het²,—(CY₂)_(p)—O—(CY₂)_(t)-Het², —(CY₂)_(p)—O—(CY₂)_(t)—NYY,—(CY₂)_(p)—O—(CY₂)_(t)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY,—(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY,—(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y, —(CY₂)_(p)—NY—SO₂—Y, and —(CY₂)_(p)—SO₂—Yare thus: —OY, —OH, —O-A, —O—CH₃, —O—CHF₂, —O—CH₂F, —O—CH₂CH₃,—(CH₂)_(p)—OY, —CH₂—O—CH₃, —CH₂—O—CH₂CH₃, —O—CH═CH₂, —CH₂—O—CH═CH₂,—O—CH₂—CH═CH₂, —CH₂—O—CH₂—CH═CH₂, —O-Het², —O—CH₂—Het², —O—CH₂CH₂—Het²,—O—CH₂—NYY, —O—CH₂CH₂—NYY, —O—CH₂—NH₂, —O—CH₂CH₂—NH₂, —O—CH₂—NHCH₃,—O—CH₂CH₂—NHCH₃, —O—CH₂—OY, —O—CH₂CH₂—OY, —O—CH₂CH₂CH₂—OY, —O—CH₂—OH,—O—CH₂CH₂—OH, —O—CH₂CH₂CH₂—OH, —O—CH₂—OA, —O—CH₂CH₂—OA, —O—CH₂CH₂CH₂—OA,—O—CH₂—OCH₃, —O—CH₂CH₂—OCH₃, —O—CH₂CH₂CH₂—OCH₃, —O—CH₂—SO₂—Y,—O—CH₂—SO₂—CH₃, —NYY, —NH₂, —NHA, —NAA, —NHCH₃, —N(CH₃)₂, —CH₂—NYY,—CH₂—NH₂, —CH₂—NHA, —CH₂—NAA, —CH₂—NHCH₃, —CH₂—N(CH₃)₂, —COOY, —COOA,—CH₂—COOY, —CH₂—COOA, —CH₂—COOCH₃, —CO—NYY, —CO—NAA, —CO—NHA,—CO—NH—CH₃, —CH₂—CO—NYY, —CH₂—CO—NAA, —(CH₂)_(p)—NY—COY,—(CH₂)_(p)—NY—COA.

Correspondingly, the invention relates to the compounds of the formula(I) in which at least one of the said radicals has one of the meaningsindicated above. Radicals not indicated in greater detail in the contextof one of the formula (I), sub-formulae thereof or any residue thereonare intended to have the meaning indicated in the case of the formula(I), as disclosed herein, in order to achieve the object of theinvention. This means that the said radicals can adopt all meaningsascribed to them as described above or below, including all preferredembodiments, without being restricted thereto and independently of theiroccurrence in another particular context. In particular, it goes withoutsaying that each embodiment of a certain radical can be combined witheach embodiment of one or more other radicals.

In an illustrative embodiment:

-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted, independently of one    another, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY and/or    —SO₂—Het²,-   HET denotes a 5- or 6-membered aromatic heterocycle having 1, 2 or 3    N atoms and optionally an O atom or S atom, where this heterocycle    is linked to the N atom of the skeleton via a ring C atom and where    this heterocycle may be unsubstituted or substituted by one, two or    three substituents, which are selected, independently of one    another, from the group consisting of: Hal, A, Het², CN,    —(CY₂)_(p)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,    —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY or —SO₂—Het²; and may be part    of a bicyclic 11- or 12-membered aromatic heterocycle, where this    bicyclic aromatic heterocycle may overall be unsubstituted or    substituted by one, two, three or more substituents, which are    selected, independently of one another, from the group consisting    of: Hal, A, Het², —CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,    —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY or —SO₂—Het²,-   Hal denotes F, Cl, Br or I,-   p denotes, independently of one another, 0, 1, 2, 3, 4, 5 or 6 and-   t denotes 1, 2, 3, 4, 5 or 6.

Compounds of the formula (I) where R3=A can also be depicted as follows:

where it is to be understood that the groups A can have the same ordifferent meaning.

In preferred embodiments of the compounds of the formula (I) or (IA), R1stands for unsubstituted or substituted C₁-C₃-alkyl, particularlypreferably methyl. Correspondingly, the present invention providespreferred compounds of the following formulae (II):

and the alternatives where R3=H.

In preferred embodiments of the compounds of the formulae (I) or (IA)and (II), R3 denotes H or, more preferably, unbranched or branched alkylhaving 1, 2, or 3 C atoms, where 1, 2, 3, 4, or 5 H atoms may bereplaced, independently of one another, by Hal. R3 particularlypreferably denotes methyl. The present invention thus also providescompounds of the following formulae (III) and (IV):

In each of the formulae (I), (II), (III) and (IV), Het¹ is preferably amonocyclic heteroaryl having 2, 3, or 4 C atoms and 1, 2, or 3 N atoms,which may be unsubstituted or substituted as given defined in compoundhaving formula (I). Het¹ (in each of the formulae shown) is furthermoreparticularly preferably selected from pyridinyl, pyrimidinyl, pyrazolyl,triazolyl and imidazolyl, which may be unsubstituted or substituted asdefined above, where pyrazolyl and triazolyl, in particular1,2,3-triazolyl, are particularly preferred.

Het¹ can be, for example, unsubstituted or substituted by one or twosubstituents, which are preferably selected, independently of oneanother, from: Hal, A, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, and -Het²,particularly preferably alkyl, which may be unsubstituted or mono- orpolysubstituted by halogen, in particular F; —OY, —NYY, halogen, and-Het², particularly preferably methyl, ethyl, amino, methoxy,fluoromethyl, difluoromethyl, fluorine, azetidinyl, where methyl andethyl are particularly preferred.

Het¹ (in each of the formulae shown) is particularly preferably selectedfrom: 1H-pyrazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-3-yl,1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoromethyl-1H-pyrazol-4-yl, 1-difluoromethyl-1H-pyrazol-4-yl,1,3-dimethyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-ethyl-3-methyl-1H-pyrazolyl, 3-fluoro-1-methyl-1H-pyrazol-4-yl,3-amino-1H-pyrazol-5-yl, 2H-1,2,3-triazol-4-yl, 3H-1,2,3-triazol-4-yl-,1-methyl-1H-1,2,3-triazol-4-yl, 2-methyl-2-H1,2,3-triazol-4-yl,2-amino-1H-imidazol-4-yl, 6-methoxypyridin-3-yl, and1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl. Het¹ is very preferablypyrazolyl, which may be unsubstituted or substituted as defined above,and can be selected, for example, from 1H-pyrazol-4-yl, 2H-pyrazol-3-yl,1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoromethyl-1H-pyrazol-4-yl, 1-difluormethyl-1H-pyrazol-4-yl,1,3-dimethyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-ethyl-3-methyl-1H-pyrazolyl, 3-fluoro-1-methyl-1H-pyrazol-4-yl,3-amino-1H-pyrazol-5-yl, where 1H-pyrazol-4-yl, 2H-pyrazol-3-yl,1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoromethyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl,1-ethyl-1H-pyrazol-4-yl and are particularly preferred. Alternatively,Het¹ is preferably triazolyl, which may be unsubstituted or substitutedas defined above, and can be selected, for example, from2H-1,2,3-triazol-4-yl, 3H-1,2,3-triazol-4-yl-,1-methyl-1H-1,2,3-triazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl,particularly preferably 2-methyl-2H-1,2,3-triazol-4-yl.

In other embodiments of the compounds of one of each of the of theformulae (I), (II), (III) and (IV), Het¹ can be a bicyclic heteroarylhaving 6, 7 or 8 C atoms and 1, 2, or 3 N atoms sein, which may beunsubstituted or substituted as defined above. Preferred substituentsare, analogously to the monocyclic heteroaryls, Hal, A, —(CY₂)_(p)—OY,—(CY₂)_(p)—NYY, and -Het², particularly preferably alkyl. For example,Het¹ can be selected from bezimidazolyl, imidazo[4,5-b]pyridinyl,benzodiazolyl, which may be unsubstituted or substituted as mentioned aspreferred in relation to formula (I) and above, preferably, for example,2-methyl-3H-benzimidazol-5-yl, 3H-benzimidazol-5-yl,2-methyl-1H-imidazo[4,5-b]pyridin-6-yl.

In preferred embodiments of compounds of one of each of the of theformulae (I), (II), (III) and (IV), HET is selected from the followingaromatic heterocycles, which may in each case be unsubstituted orsubstituted as defined above:

HET denotes, irrespective of possible substitution, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-3,4-diazolyl,1-oxa-2,5-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1,2,3-triazolyl,1,3,4-triazolyl, and tetrazolyl; pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl; indolyl, isoindolyl, benzimidazolyl, indazolyl,benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, imidazo[4,5-b]pyridinyl,imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl,pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,pyrazolo[3,4-b]pyridinyl, purinyl, indozilinyl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrrolo[1,2-b]-pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl,1,6-naphtyridinyl, 1,7-naphtyridinyl, 1,8-naphtyridinyl,1,5-naphtyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-d]pyrazinyl, pyrido[3,4-b]-pyrazinyl,pyrazino[2,3-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,pyrimido[4,5-d]pyrimidinyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, furopyridinyl, and thienopyridinyl.

HET is particularly preferably selected from the following 5- or6-membered monocyclic aromatic heterocycles, which may in each case beunsubstituted or substituted as defined above: pyridinyl, pyrimidinyl,pyrazolyl, thiazolyl, imidazolyl.

These preferences for HET also apply, in particular, to compounds of theformulae (I), (II), (III), (IV), in combination with the preferredembodiments for Het¹, in particular the selection of Het¹ frompyridinyl, pyrimidinyl, pyrazolyl, triazolyl and imidazolyl, as well asbezimidazolyl, imidazo[4,5-b]pyridinyl, benzodiazolyl, which may in eachcase be unsubstituted or substituted as defined above, for example1H-pyrazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-3-yl,1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoromethyl-1H-pyrazol-4-yl, 1-difluormethyl-1H-pyrazol-4-yl,1,3-dimethyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-ethyl-3-methyl-1H-pyrazolyl, 3-fluoro-1-methyl-1H-pyrazol-4-yl,3-amino-1H-pyrazol-5-yl, 2H-1,2,3-triazol4-yl, 3H-1,2,3-triazol-4-yl-,1-methyl-1H-1,2,3-triazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl,2-amino-1H-imidazol-4-yl, 6-methoxypyridin-3-yl, and1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl,2-methyl-3H-benzimidazol-5-yl, 3H-benzimidazol-5-yl,2-methyl-1H-imidazo[4,5-b]pyridin-6-yl, and especially and in particularalso to embodiments in which Het¹ stands for pyrazolyl, which may beunsubstituted or substituted as defined above and can be selected, forexample, from 1H-pyrazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-3-yl,1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoromethyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl,1-ethyl-1H-pyrazol-4-yl.

Of the possible substituents on HET, preference is given to: Hal, inparticular F, Cl; A, in particular methyl, ethyl, propyl; Het², inparticular azetidinyl, tetrahydropyranyl, piperazinyl; CN;—(CY₂)_(p)—OY, —(CY₂)_(p)—OA, —(CY₂)_(p)—OH, preferably in each casewhere p=0, 1, 2, 3; —(CY₂)_(p)—OZ, —(CY₂)_(p)—O-Het², —O-Het²,—(CY₂)_(p)—O—(CY₂)_(t)-Het², —O—(CY₂)_(t)-Het², —O—(CH₂)_(t)-Het²,—(CY₂)_(p)—O—(CY₂)_(t)—NYY, —O—(CY₂)_(t)—NYY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,—O—(CY₂)_(t)—OY, —O—(CY₂)_(t)—OA, —O—(CY₂)_(t)—OH, —O—(CH₂)_(t)—OA,—O—(CH₂)_(t)—OH, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—CO—NHA, CyA,—(CY₂)_(p)—O—(CY₂)_(t)—SO₂—Y, —O—(CY₂)_(t)—SO₂—Y, —O—(CY₂)_(t)—SO₂-A,—(CY₂)_(p)—SO₂—Y, —(CY₂)_(p)—SO₂-A.

For example, the aromatic heterocycles HET generally, and the preferredembodiments in particular, for example pyridinyl, pyrimidinyl,pyrazolyl, thiazolyl, imidazolyl, may in each case be substituted byone, two, three or more substituents, which are selected, independentlyof one another, from the group consisting of: F, Cl, methyl, ethyl,propyl, isopropyl, methoxy, ethoxy, propoxy, piperazinyl,tetrahydropyranyl, —CN, 2-methoxyethoxy, 2-hydroxyethoxy, fluoromethoxy,difluoromethoxy, N-methylcarbamoyl (—C(═O)—NH—CH₃),2-methylamino-ethoxy, 1-methyl-azetidin-3-ylmethoxy, trideuteriomethoxy,trifluoromethoxy, methylsulfonylmethoxy, methylsulfonyl, cyclopropyl,allyloxy, piperazinyl, and azetidinyloxy. No, mono- or disubstitutionare preferred.

A preferred embodiment of HET is unsubstituted or substituted pyridinyl,for example mono- or disubstituted pyridinyl. Monosubstituted pyridinylsare preferably substituted in position 3 of the pyridine ring and linkedvia positions 2 or 4, disubstituted pyridinyls are preferablysubstituted in positions 3 and 5 of the pyridine ring and linked viapositions 2 or 4. This preferred embodiment can advantageously becombined with the preferred embodiments of Het¹, in particular thepreferred embodiments in which Het¹ is unsubstituted or substitutedpyrazolyl or alternatively unsubstituted or substituted triazolyl, andin particular with the above-mentioned particularly preferredembodiments.

In other preferred embodiments, HET is an unsubstituted, but preferablymono- or disubstituted pyrazole. This embodiment too can advantageouslybe combined with the preferred embodiments of Het¹, in particular thepreferred embodiments in which Het¹ is unsubstituted or substitutedpyrazolyl or alternatively unsubstituted or substituted triazolyl, andin particular with the above-mentioned particularly preferredembodiments.

In a further preferred embodiment, HET is an unsubstituted, butpreferably monosubstituted pyrimidine, where the pyrimidine ispreferably substituted in position 5 and linked via positions 2 or 4.This embodiment too can advantageously be combined with the preferredembodiments of Het¹, in particular the preferred embodiments in whichHet¹ is unsubstituted or substituted pyrazolyl or alternativelyunsubstituted or substituted triazolyl, and in particular with theabove-mentioned particularly preferred embodiments.

In preferred embodiments of one of each of the formulae (I), (II),(III), (IV), HET can be selected, for example, from the following 5- or6-membered monocyclic aromatic heterocycles: pyridin-2-yl, pyridin-4-yl,5-allyloxy-3-fluoropyridin-2-yl,5-(azetidin-3-yloxy)-3-fluoropyridin-2-yl,5-chloro-3-fluoropyridin-2-yl, 3-cyclopropylpyridin-4-yl,3-cyclopropyl-5-fluoropyridin-4-yl, 3,5-difluoropyridin-2-yl,3,5-difluoropyridin-4-yl, 5-difluoromethoxy-3-fluoropyridin-2-yl,3-difluoromethoxy-5-fluoropyridin-4-yl, 5-ethoxy-3-fluoropyridin-2-yl,3-fluoro-5-(1-methylazetidin-3-ylmethoxy)pyridin-2-yl,3-fluoro-5-methoxypyridin-4-yl, 3-fluoro-5-methoxypyridin-2-yl,3-fluoro-5-fluoromethoxypyridin-2-yl,3-fluoro-5-fluoromethoxypyridin-4-yl, 3-fluoropyridin-2-yl,3-fluoro-5-methylsulfonylmethoxypyridin-2-yl,3-fluoro-5-methylsulfonylpyridin-2-yl3-fluoro-5-(2-methylaminoethoxy)pyridin-2-yl,3-fluoro-5-methylpyridin-4-yl, 3-fluoro-5-methylpyridin-2-yl,3-fluoropyridin-4-yl, 3-fluoropyridin-2-yl,3-fluoro-5-piperazin-1-ylpyridin-2-yl, 3-chloropyridin-4-yl,3-ethylpyridin-4-yl, 3-ethyl-5-fluoropyridin-4-yl,3-ethyl-5-methylpyridin-4-yl, 5-fluoropyridin-2-yl,3-methylpyridin-4-yl, 3-methoxypyridin-4-yl, 2-cyanopyridin-4-yl,3-cyanopyridin-4-yl, 3-cyanopyridin-6-yl, 3-cyano-5-fluoropyridin-4-yl,3-fluoro-5-(2-methoxyethoxy)pyridin-2-yl,3-fluoro-5-(2-hydroxyethoxy)pyridin-2-yl,3-fluoro-5-(trideuteriomethoxy)pyridin-4-yl,3-fluoro-5-(trideuteriomethoxy)pyridin-2-yl,5-fluoro-3-(N-methylcarbamoyl)pyridin-6-yl, 5-fluoropyrimidin-2-yl,5-fluoropyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl,1-ethyl-3-methyl-1H-pyrazol-4-yl, 1,2-dimethyl-1H-pyrazol-4-yl,1,3-dimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl,3-methyl-1H-pyrazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl,3-fluoro-1-methylpyrazol-4-yl, thiazol-2-yl, 2-methylthiazol-4-yl, and1-methyl-1H-imidazolyl. Particular preference is given to:5-chloro-3-fluoropyridin-2-yl, 3,5-difluoropyridin-2-yl,3,5-difluoropyridin-4-yl, 5-difluoromethoxy-3-fluoropyridin-2-yl,3-difluoromethoxy-5-fluoropyridin-4-yl, 5-ethoxy-3-fluoropyridin-2-yl,3-fluoro-5-methoxypyridin-4-yl, 3-fluoro-5-methoxypyridin-2-yl,3-fluoro-5-fluoromethoxypyridin-2-yl,3-fluoro-5-fluoromethoxypyridin-4-yl, 3-fluoropyridin-2-yl,3-fluoro-5-methylsulfonylmethoxypyridin-2-yl,3-fluoro-5-methylpyridin-4-yl, 3-fluoro-5-methylpyridin-2-yl,3-fluoropyridin-4-yl, 3-ethylpyridin-4-yl, 3-ethyl-5-fluoropyridin-4-yl,3-methylpyridin-4-yl, 3-methoxypyridin-4-yl,3-fluoro-5-(2-methoxyethoxy)pyridin-2-yl,3-fluoro-5-(2-hydroxyethoxy)pyridin-2-yl,3-fluoro-5-(trideuteriomethoxy)pyridin-4-yl,3-fluoro-5-(trideuteriomethoxy)pyridin-2-yl, 5-fluoropyrimidin-2-yl,5-fluoropyrimidin-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-4-yl, 1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl, and2-methylthiazol-4-yl.

The preference for the above-mentioned 5- or 6-membered monocyclicaromatic or heterocycles also applies, in particular, to compounds ofthe formulae (I), (II), (III), (IV) in combination with the preferredembodiments for Het¹, in particular the selection of Het¹ frompyridinyl, pyrimidinyl, pyrazolyl, triazolyl and imidazolyl, which maybe unsubstituted or substituted as defined above and especially and inparticular also to the embodiments in which Het¹ stands for pyrazolyl,which may be unsubstituted or substituted as defined above and can beselected, for example, from the examples explicitly mentioned above.They also apply, in particular, to the embodiments in which Het¹ standsfor triazolyl, and can be selected, for example, from the examplesexplicitly mentioned above.

In other illustrative embodiments of one of each of the formulae (I),(II), (III), (IV), HET can be selected from pyrrolo[3,2-c]pyridinyl,pyrrolo[2,3-b]pyridinyl and quinolinyl, which may in each case beunsubstituted or substituted as mentioned for compound (I) and inparticular for the monocyclic preferred embodiments. Examples are1H-pyrrolo[3,2-c]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl or5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl, in each case in particular alsoin each case in combination with one of the preferred embodiments ofHet¹ mentioned above.

Very particular preference is given to the compounds shown in Table 1below, and pharmaceutically usable derivatives, salts, solvates,tautomers and/or stereoisomers thereof, or free forms including mixturesthereof in all ratios.

TABLE 1 Particularly preferred compounds

1-(3,5-Difluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(3,5-Difluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1,8-Bis(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-2-yl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

1-(3-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoropyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

7-Methoxy-3-methyl-1-(3-methylpyridin-4-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylpyridin-2-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1,8-bis(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-fluoropyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-fluoropyridin-4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylpyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

7-Methoxy-1-(3-methoxypyridin-4-yl)-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(5-methyl-1H-pyrazol-3-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1-(2-methylthiazol-4-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(5-Fluoropyrimidin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H,2H,3H-imidazo[4,5-c]quinolin-2-one hydrochloride

7-Methoxy-1-(3-methoxypyridin-4-yl)-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-fluoropyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1-(3-methylpyridin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(5-Fluoropyrimidin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1-[1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl]-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

7-Methoxy-3-methyl-1-(3-methyl-1H-pyrazol-4-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

5-Fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl] nicotinonitrile

4-[7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]pyridine-2-carbonitrile

4-[7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]nicotinonitrile

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-thiazol-2-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

6-[7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]nicotinonitrile

7-Methoxy-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

1-(5-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-pyrimidin-2-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-methylpyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-[1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl]-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-pyridin-2-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-pyrimidin-5-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-pyridin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1-(1-methyl-1H-imidazol-4-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(3-Chloropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-methylpyridin-4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1-pyridin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-(3-Fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(3-Amino-1H-pyrazol-5-yl)-1-(3-fluoro-2-pyridyl)-7-methoxy-3-methylimidazo[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(2-methoxyethoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2- one

1-[3-Fluoro-5-(2-hydroxyethoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-quinolin-2-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-(1H-pyrrolo[2,3-b]pyridin-6-yl)1,3-dihydroimidazo[4,5-c]quinolin- 2-one

1-(3,5-Difluoropyridin-2-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-(3-Fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-7-methoxy-1-(3-methoxypyridin-4-yl)-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy-pyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(3,5-Difluoropyridin-2-yl)-7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-2-yl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(2H-pyrazol-3-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-fluoromethoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(3-Ethyl-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one

1-(5-Ethoxy-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(5-Difluoromethoxy-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Difluoropyridin-2-yl)-7-methoxy-3-methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3,5-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(5-Chloro-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-(1H-pyrrolo[3,2-c]pyridin-6-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-3-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(3-Fluoro-5-piperazin-1-yl-pyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(2H-pyrazol-3-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Ethyl-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(3H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(2-methyl-3H-benzoimidazol-5-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(3H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinoline- one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(2-methyl-3H-benzoimidazol-5-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2- one

5-Fluoro-6-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-N-methyl- nicotinamide

6-[8-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-5-fluoro-N-methylnicotinamide

1-(3-Fluoro-5-methoxypyridin-4-yl)-8-(1-fluoromethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(3-Fluoro-1-methyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

8-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Difluoromethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-8-(2-methyl-3H-benzoimidazol-5-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-[3-Fluoro-5-(trideuteriomethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one

1-(3-Difluoromethoxy-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Difluoromethoxy-5-fluoropyridin-4-yl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Fluoro-5-fluoromethoxypyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-fluoro-methoxypyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

8-(1,3-Dimethylpyrazol-4-yl)-1-[3-fluoro-5-(trideuterio-methoxy)-4-pyridyl]-7-methoxy-3-methylimidazo[4,5-c]- quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(4-methyl-1H-pyrazol-3-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

8-(3H-Benzimidazol-5-yl)-1-(3-fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(trideuteriomethoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one

1-(3-Ethylpyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1-Ethyl-1H-pyrazol-4-yl)-1-(3-ethylpyridin-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(3-Fluoro-1-methyl-1H-pyrazol-4-yl)-7-methoxy-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydroimidazo[4,5-c]- quinolin-2-one

1-(3-Cyclopropylpyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one

1-(3-Fluoro-5-methylsulfonylmethoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Cyclopropyl-5-fluoropyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin- 2-one

8-(1,3-Dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methyl-sulfonylmethoxypyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

1-(5-Allyloxy-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2- one

1-[5-(Azetidin-3-yloxy)-3-fluoropyridin-2-yl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(2-methylaminoethoxy)-pyridin-2-yl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(1-methylazetidin-3-ylmethoxy)pyridin-2-yl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

8-[1-(Azetidin-3-yl)-1H-pyrazol-4-yl]-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1H,2H,3H-imidazo[4,5-c]- quinolin-2-one

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

1-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(trifluoromethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-[3-Fluoro-5-(trifluoromethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1,3-dimethylpyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one

1-(3-Fluoro-5-methylsulfonylpyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H,2H,3H-imidazo-[4,5-c]quinolin-2-one

8-[1-(Azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl]-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-1H,2H,3H-imidazo[4,5-c]quinolin-2-one

Each of the meanings for R1, R3, HET, and Het1 disclosed in the contextof the above preferred compounds is also to be regarded as preferredmeaning of the corresponding radical, irrespective of the othersubstitution of the molecule's basic structure, i.e. as possiblemeanings of R1, R3, HET, and Het1 in each case independently of oneanother.

Preparation

The compounds of the formula (I) and also the starting materials fortheir preparation are prepared by methods known per se, as described inthe literature (for example in standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart) and/or are known to the person skilledin the art, and under reaction conditions which are known and suitablefor the said reactions. Use can also be made of variants known per sewhich are not mentioned in greater detail here. The compounds accordingto the invention can be prepared by means of or analogously to thesyntheses described in detail in EXAMPLES 1 to 13 through suitablechoice or adaptation of the starting materials. For most compoundsaccording to the invention, the synthesis described in Example 1 can besuitably modified and thus employed analogously. Amine derivatives andboronic acid esters or analogues which can be employed in thecorresponding syntheses are summarised below in Scheme 4. In addition,reference is also made to the disclosure WO 2010/139731, which is to beincorporated in its full scope into the present disclosure by way ofreference.

The process and the subsequent work-up of the reaction mixture canbasically be carried out as a batch reaction or in continuous reactionprocedure. The continuous reaction procedure comprises, for example, thereaction in a continuous stirred-tank reactor, a stirred-tank cascade, aloop or cross-flow reactor, a flow tube or in a microreactor. Thereaction mixtures are optionally worked up, if necessary, by filtrationthrough solid phases, chromatography, separation between immisciblephases (for example extraction), adsorption onto solid supports,distilling off solvents and/or azeotropic mixtures, selectivedistillation, sublimation, crystallisation, co-crystallisation or bynanofiltration on membranes.

The starting compounds are generally known. If they are novel, they canbe prepared by methods known per se. If desired, the starting materialscan be formed in situ by not isolating them from the reaction mixture,but instead immediately converting them further into the compoundsaccording to the invention. It is likewise possible to carry out thereaction stepwise.

Pharmaceutically Usable Forms

For the purposes of the invention, the compounds according to theinvention are defined in such a way that they also includepharmaceutically usable derivatives, salts, solvates including hydrates,precursors of the compounds, tautomers and optically active forms (suchas, for example, stereoisomers, diastereomers, enantiomers, racemates).The invention also relates to the use of mixtures of the compounds ofthe formula (I), for example mixtures of two diastereomers, for examplein the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. They areparticularly preferably mixtures of stereoisomeric compounds.

Solvates of the compounds are taken to mean adductions of inert solventmolecules onto the compounds which form owing to their mutual attractiveforce. Solvates are, for example, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and so-calledprecursors or prodrugs of the compounds. Prodrugs or precursors aretaken to mean, for example, compounds of the formula (I) modified bymeans of alkyl or acyl groups, sugars or oligopeptides, which arerapidly cleaved in the organism to give the effective compoundsaccording to the invention. These also include biodegradable polymerderivatives of the compounds according to the invention, as described,for example, in Int. J. Pharm. 115, 61-67 (1995). Any compound which canbe converted in vivo into a bioactive agent, i.e. compounds of theformula (I), is a precursor in the sense of this invention. Anybiologically active compound which results from the in vivometabolisation of a compound according to the invention is a metabolitein the sense of the present invention.

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds according to theinvention are for the most part prepared by conventional methods. If thecompounds contain a carboxyl group, one of its suitable salts can beformed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides (for example potassium hydroxide, sodium hydroxide andlithium hydroxide), alkaline-earth metal hydroxides (for example bariumhydroxide and calcium hydroxide), alkali metal alkoxides (for examplepotassium ethoxide and sodium propoxide) and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. A base can beconverted into the associated acid-addition salt using an acid, forexample by reaction of equivalent amounts of the base and the acid in aninert solvent, such as, for example, ethanol, and subsequentevaporation. Suitable acids for this reaction are, in particular, thosewhich give physiologically acceptable salts, such as, for example,hydrogen halides (for example hydrogen chloride, hydrogen bromide orhydrogen iodide), other mineral acids and corresponding salts thereof(for example sulfate, nitrate or phosphate and the like), alkyl- andmonoarylsulfonates (for example ethanesulfonate, toluenesulfonate andbenzenesulfonate) and other organic acids and corresponding saltsthereof (for example acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like. Saltswith physiologically unacceptable acids, for example picrates, can beused for the isolation and/or purification of the compounds according tothe invention.

With regard to that stated above, it can be seen that the expression“pharmaceutically usable salt”, or also “pharmaceutically acceptablesalt” in the present connection is to be taken to mean a compoundaccording to the invention which is in the form of one of its salts, inparticular if this salt form of the compound imparts improvedpharmacokinetic properties compared with its free form. Thepharmaceutically acceptable salt form of the compound may also providethis compound with a desired pharmacokinetic property for the first timeand can even have a positive influence on the pharmacodynamics of thecompound with respect to its therapeutic efficacy in the body.

Compounds according to the invention may be chiral owing to theirmolecular structure and accordingly occur in various enantiomeric forms.They can therefore exist in racemic or in optically active form. Sincethe pharmaceutical activity of the racemates or stereoisomers of thecompounds of the formula I may differ, it may be desirable to use theenantiomers. In these cases, the end product or even the intermediatecan be separated into enantiomeric compounds by chemical or physicalmeasures known to the person skilled in the art or even employed as suchin the synthesis.

It is generally known that atoms can have atomic masses or mass numberswhich can differ from the usual naturally occurring atomic masses ormass numbers. Examples of isotopes which are commercially available andwhich can be incorporated into a compound according to the invention byknown methods are isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, for example ²H, ³H, ¹³O, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P ³⁵S, ¹⁸F and ³⁶Cl. The incorporation of heavierisotopes, in particular deuterium (²H), into a compound according to theinvention has therapeutic advantages which have their roots in thehigher metabolic stability of this isotope-labelled compound. Highermetabolic stability directly results in an increased in vivo half life,which enables a lower dosage.

The definitions of the atoms H, C, N, etc., as used in the compoundsaccording to the invention, therefore also relate to the heavierisotopes of these atoms.

Particular preference is given in accordance with the invention to theuse of D (deuterium, ²H) instead of hydrogen (¹H). Deuterium can beincorporated into the compounds according to invention, for example, bymeans of a suitable substituent on HET for example trideuteriomethyl ortrideuteriomethoxy.

Use

It has surprisingly been found that the compounds according to theinvention effect specific inhibition of protein kinases, especially ATMkinase. Correspondingly, the present invention provides ATM inhibitorswhich are selected from the compounds according to the invention.

As part of the invention presented here, novel2,3-dihydro-1H-imidazol[4,5-c]quinoline compounds were provided for thefirst time. The compounds according to the invention controlserine/threonine protein kinases, in particular ATM kinase, affinitivelyand/or selectively. The compounds of the formula (I) and derivativesthereof are distinguished by high specificity and stability, lowpreparation costs and easy handling. Such properties form the basis fora reproducible mode of action and reliable and safe interaction with thecorresponding target structures. The invention also includes the use ofthe present 2,3-dihydro-1H-imidazol[4,5-c]quinoline derivatives for theinhibition, regulation and/or modulation of the signalling cascade ofserine/threonine protein kinases, in particular ATM kinase, and thusoffers novel tools for research and/or diagnostics.

The invention therefore furthermore relates to the use of compoundsaccording to the invention and/or physiologically acceptable solvates,salts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, for the inhibition of serine/threonine proteinkinases, in particular ATM kinase. The term “inhibition” relates to anyreduction in the activity which is based on the action of the specificcompounds according to the invention in that the latter are capable ofinteracting with the target molecule in such a way that recognition,binding and blocking is made possible. The compounds are distinguishedby high affinity to ATM kinase, ensuring reliable binding and preferablycomplete blocking of the kinase activity. The compounds are furthermorevery selective and thus enable exclusive and direct recognition of ATMkinase. The term “recognition” relates here to any type of interactionbetween the compound and the said target molecules, in particularcovalent or non-covalent bonds, such as, for example, a covalent bond,hydrophobic/hydrophilic interactions, van der Waals forces, ionattraction, hydrogen bonds, ligand/receptor interactions, base pairs ofnucleotides or interactions between epitope and antibody binding site.

Compounds according to the invention and/or physiologically acceptablesalts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, are suitable for use in the treatment of diseasewhich are caused, mediated and/or propagated by the activity ofserine/threonine protein kinases, in particular ATM.

The present invention relates to the compounds according to theinvention and/or physiologically acceptable derivatives, solvates,salts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, for use as medicament.

The invention discloses the compounds according to the invention and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, for use in thetreatment of diseases which are caused, mediated and/or propagated bythe activity of serine/threonine protein kinases, in particular ATMkinase.

The present invention therefore also relates to the compounds accordingto the invention and/or physiologically acceptable derivatives,solvates, salts, tautomers and/or stereoisomers thereof, includingmixtures thereof in all ratios, for use in the treatment of diseaseswhich are caused, mediated and/or propagated by the activity ofserine/threonine protein kinases, in particular ATM kinase. The presentinvention correspondingly also relates to the use of compounds accordingto the invention and/or physiologically acceptable derivatives,solvates, salts, tautomers and/or stereoisomers thereof, includingmixtures thereof in all ratios, for the preparation of a medicament forthe treatment of diseases which are caused, mediated and/or propagatedby the activity of serine/threonine protein kinases, in particular ATMkinase. In other words, the present invention also discloses a compoundaccording to the invention and/or a pharmaceutically usable derivative,salt, solvate, tautomer or stereoisomer thereof, for use in thetreatment of diseases which are influenced by inhibition of ATM kinase.

For the identification of a corresponding signalling pathway and inorder to detect interactions between various signalling pathways,suitable models or model systems have been developed, for example cellculture models (Khwaja et al. (1997) EMBO 16: 2783) and models oftransgenic animals (White et al. (2001) Oncogene 20: 7064). In order todetermine certain stages in the signalling cascade, interactingcompounds can be used in order to modulate the signal (Stephens et al.(2000) Biochemical J 351: 95). In addition, the compounds according tothe invention can also be used as reagents for testing kinase-dependentsignalling pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application. As discussed herein,these signalling pathways are relevant for various diseases.Accordingly, the compounds according to the invention are useful in theprophylaxis, therapy and/or progress control of diseases which aredependent on signalling pathways with participation by serine/threonineprotein kinases, preferably ATM kinase.

The present invention also relates to the compounds according to theinvention and/or physiologically acceptable derivatives, solvates,salts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, for use in the treatment of cancer, tumoursand/or metastases and to the use thereof in the preparation of amedicament for precisely these uses.

The tumour is selected, in particular, from the group of diseases of thesquamous epithelium, bladder, stomach, kidneys, head, neck, oesophagus,cervix, thyroid, intestine, liver, brain, prostate, urogenital tract,lymphatic system, larynx, lung, skin, blood and immune system, and/orthe cancer is selected from the group of monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinoma, pancreatic cancer,glioblastoma, bowel carcinoma, breast carcinoma, acute myeloidleukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chroniclymphatic leukaemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

The present invention additionally relates to a process for thepreparation of a medicament, preferably for use in the treatment ofcancer and/or tumours, preferably the types of cancer or tumourmentioned above, comprising:

-   i. determination that a concentration at which a compound according    to the invention and/or a pharmaceutically usable derivative, salt,    solvate, tautomer or stereoisomer thereof achieves 50% inhibition of    the activity of ATM kinase is 500 nM or less, preferably 100 nM, 10    nM, 1 nM or less, and-   ii. preparation of a pharmaceutical composition which comprises the    compound.

The determination of 50% inhibition of the activity of ATM kinase ispreferably carried out here with the aid of the assay described herein(IC50 ATM).

Compounds according to the invention and/or physiologically acceptablederivatives, solvates, salts, tautomers and/or stereoisomers thereof,including mixtures thereof in all ratios, may also be suitable for usein the slowing of ageing processes, where the slowing occurs withreference to the comparison of the life span of the treated host orcells, cell cultures, tissues or organs thereof with correspondingpositive of negative controls and/or statistics.

The invention furthermore teaches a method for the treatment of cancer,tumours and/or metastases in which an effective amount of at least onecompound according to the invention and/or physiologically acceptablederivatives, solvates, salts, tautomers and/or stereoisomers thereof,including mixtures thereof in all ratios, is administered to a subjectto be treated. Preferred subjects in the sense of the invention arehumans or animals, particularly preferably humans. It is known to theperson skilled in the art here that he can administer the compoundsaccording to the invention, which can of course also be used as thepharmaceutical composition according to the invention, in various dosesto an organism, in particular a human patient. The effective amount andthe type of administration can be determined by the person skilled inthe art by routine experiments. The previous teaching of the inventionand embodiments thereof are valid and can be applied withoutrestrictions to the treatment method, if it appears appropriate.

The compounds according to the invention, salts, isomers, tautomers,enantiomers, diastereomers, racemates, derivatives, prodrugs and/ormetabolites thereof are effective not only in the case of the saidclinical pictures, but likewise in the diagnosis and therapy of alldiseases in connection with the ATM signalling cascade, especially witha view to inhibition of cell proliferation and migration.

In addition, the inhibitors according to the invention can be used inthe treatment of retroviral diseases by suppression of retroviralintegration (R. Daniel (1999) Science 284: 644). Finally, the inhibitorsaccording to the invention can be employed as immunomodulators andmodulators of telomere maintenance.

The present invention furthermore relates to the use of a compoundaccording to the invention and/or pharmaceutically usable derivative,salt, solvate, tautomer or stereoisomer thereof for the inhibition of aprotein kinase, in particular ATM kinase in vitro.

The said use of compounds according to the invention and/orpharmaceutically usable derivatives, solvates, salts, tautomers and/orstereoisomers thereof, including mixtures thereof in all ratios, for theinhibition of serine/threonine protein kinases, in particular ATMkinase, can take place in in vitro or in vivo models. The susceptibilityof a particular cell to treatment with the compounds according to theinvention can be determined by testing in vitro. Typically, a culture ofthe cell is incubated with a compound according to the invention atvarious concentrations for a period of time which is sufficient toenable the active agents to induce cell death or to inhibit cellproliferation, cell vitality or migration, usually between about onehour and one week. For testing in vitro, cultivated cells from a biopsysample can be used. The amount of cells remaining after the treatment isthen determined. The use in vitro takes place, in particular, on samplesof mammal species which are suffering from cancer, tumours, metastases,angiogenesis disorders, retroviral diseases, immune diseases and/orpathogenic ageing processes. The host or patient can belong to anymammal species, for example a primate species, in particular humans, butalso rodents (including mice, rats and hamsters), rabbits, horses, cows,dogs, cats, etc. Animal models are of interest for experimentalinvestigations, providing a model for the treatment of a human disease.

The testing of a plurality of specific compounds enables the selectionof the compound or active compound which appears the most suitable forthe treatment of the patient. The in vivo dose of the selected compoundis advantageously matched to the susceptibility of the kinase and/orseverity of the disease of the patient taking into account the in vitrodata, as a result of which the therapeutic efficacy is noticeablyincreased. The dose varies depending on the specific compound used, thespecific disease, the patient status, etc. A therapeutic dose istypically sufficient considerably to reduce the undesired cellpopulation in the target tissue, while the viability of the patient ismaintained.

The teaching of the invention disclosed herein and embodiments thereofrelating to the use of compounds as or for the preparation of amedicament for the treatment is valid and can be applied withoutrestrictions to the use of the compounds for the inhibition of kinaseactivity if it appears appropriate.

The treatment is generally continued until a considerable reduction hasoccurred, for example at least about 50% reduction of the cell load, andcan be continued until essentially no more undesired cells are detectedin the body. In tests of this type, the compounds according to theinvention exhibit and cause an inhibiting effect, which is usuallydocumented by IC₅₀ values in a suitable range, preferably in themicromolar range and more preferably in the nanomolar range. The kinaseis, in particular, inhibited to the extent of 50% if the concentrationof the compounds is less than 1 μM, preferably equal to or less than 0.5μM, particularly preferably less than 0.1 μM, 0.05 μM or 0.001 μM. Thisconcentration is called the IC₅₀ value and is preferably determined withthe aid of the assay described herein (IC50 ATM). In accordance with theusual nomenclature, “μM” stands for micromoles per litre, “nM” standsfor nanomoles per litre.

Assays

The compounds according to the invention exhibit an advantageousbiological activity which can be demonstrated in the tests describedherein, such as, for example, enzyme-based assays.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (Alessi et al. (1996) FEBS Lett. 399(3): 333) or the basicmyelin protein, are described in the literature (Campos-Gonzalez &Glenney (1992) JBC 267: 14535). Various assay systems are available forthe identification of kinase inhibitors. In the scintillation proximityassay (Sorg et al. (2002) J Biomolecular Screening 7: 11) and theflash-plate assay, the radioactive phosphorylation of a protein orpeptide as substrate are measured using ATP. In the presence of aninhibitory compound, a decreased radioactive signal, or none at all, isdetectable. Furthermore, homogeneous time-resolved fluorescenceresonance energy transfer (HTR-FRET) and fluorescence polarisation (FP)technologies are useful as assay methods (Sills et al. (2002) JBiomolecular Screening 191). Other non-radioactive ELISA methods usespecific phospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody.

For the purposes of the present invention, the inhibition of theactivity of ATM is preferably determined with the aid of the followingassay:

ATM Kinase Assay—Determination of ATM Inhibition (IC50 ATM):

The IC₅₀ value was determined with the aid of a biochemical ATM kinaseassay. The assay consists of two steps: the enzymatic reaction and thedetection step. Firstly, ATM (ataxia telangiectasia mutated) protein andthe test substance are incubated at different concentrations withaddition of substrate protein p53 and ATP. ATM mediates thephosphorylation of p53 at several positions, including at amino acidS15. The amount of phosphorylated p53 is determined with the aid ofspecific antibodies and the TR-FRET technique. The enzymatic ATM assayis carried out as TR-FRET (HTRF™, Cisbio Bioassays) based 384-wellassay. In the first step, purified human recombinant ATM (human ATM,full length, GenBank ID NM_000051, expressed in a mammal cell line) isincubated in assay buffer for 15 minutes with the ATM inhibitor invarious concentrations and without test substance as negative or neutralcontrol. The assay buffer comprises 25 mM HEPES pH 8.0, 10 mMMg(CH₃COO)₂, 1 mM MnCl₂, 0.1% BSA and 0.01% Brij® 35, 5 mMdithiothreitol (DTT). The test-substance solutions were dispensed intothe microtitre plates using an ECHO 555 (Labcyte). In the second step,purified human recombinant cmyc-labelled p53 (human p53, full length,GenBank ID BC003596, expressed in Sf21 insect cells) and ATP are added,and the reaction mixture is incubated at 22° C. for 30-35 minutes. Thepharmacologically relevant assay volume is 5 μl. The finalconcentrations in the assay during incubation of the reaction mixtureare 0.3-0.4 nM ATM, 50-75 nM p53 and 10 μM ATP. The enzymatic reactionis stopped by addition of EDTA. The formation of phosphorylated p53 asthe result of the ATM-mediated reaction in the presence of ATP isdetected via specific antibodies [labelled with the fluorophoreneeuropium (Eu) as donor and d2 as acceptor (Cisbio Bioassays)] whichenable FRET. 2 μl of antibody-containing stop solution (12.5 mM HEPES pH8.0, 125 mM EDTA, 30 mM sodium chloride, 300 mM potassium fluoride,0.1006% Tween-20, 0.005% Brij® 35, 0.21 nM anti-phospho-p53(ser15)-Euantibody and 15 nM anti-cmyc-d2 antibody) are added to the reactionmixture. After incubation, usually for 2 hours (between 1.5 and 15 h),for signal development, the plates are analysed in a plate reader(EnVision, PerkinElmer) using TRF mode (and with laser excitation).After excitation of the donor europium at a wavelength of 340 nm, theemitted fluorescence light both of the acceptor d2 at 665 nm and also ofthe donor Eu at 615 nm is measured. The amount of phosphorylated p53 isdirectly proportional to the quotient of the amounts of light emitted,i.e. the relative fluorescence units (RFU) at 665 nm and 615 nm. Themeasurement data were processed by means of Genedata Screener software.IC₅₀ determinations are carried out, in particular, by fitting adose/action curve to the data points by means of nonlinear regressionanalysis.

IC₅₀=half-maximum inhibitory concentration

ATP=adenosine triphosphate

TR-FRET=time-resolved fluorescence resonance energy transfer

HTRF®=homogeneous time resolved fluorescence

HEPES=2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid

Mg(CH₃COO)₂=magnesium acetate

MnCl₂=manganese(II) chloride

BSA=bovine serum albumin

EDTA=ethylenediamine tetraacetate

TRF=time resolved fluorescence

The activity of the substances according to the invention in thecellular environment can be determined with the aid of the followingassay:

Cellular pCHK2 Assay:

For the identification of substances which inhibit the phosphorylationof the protein kinase CHK2 at the amino acid threonine 68, animmunofluorescence-based “high content” analysis assay was used inHCT116 cells.

In vitro cell-based immunofluorescence assay for the identification ofinhibitors of bleomycin-induced phosphorylation of CHK2 (phospho-Thr68)in the human colon carcinoma cell line HCT116:

HCT116 cells are sown out in a defined cell density in 384-well platesin culture medium (DMEM high glucose, 2 mM GlutaMax, 1 mM Na pyruvate,10% FCS) and incubated overnight at 37° C. and 10% of CO₂. On thefollowing day, the test substances are added in a defined concentrationrange (1 nM to 30 μM) in combination with 10 μM bleomycin, where theconcentration of the solvent DMSO is kept constant at 0.5%. Afterincubation for four hours at 37° C. and 10% of CO₂, the cells are fixed(5 min, 4% formaldehyde in PBS), permeabilised (10 min, 0.2% TritonX-100 in PBS) and, after blocking of nonspecific binding sites (10% goatserum, 1% BSA in PBS), incubated overnight at 4° C. with a specificanti-pCHK2 antibody (cell signalling #2661). pCHK2 (Thr68) is determinedusing an Alexa488-labelled secondary anti-rabbit IgG antibody. Parallelstaining of DNA with propidium iodide enables determination of the cellcount. The pCHK2 signal is detected using a high-content imager(Molecular Devices IMX Ultra) and automatic image analysis using theMetaXpress software belonging to the instrument. The number of cellnuclei which have a pCHK2 signal above a defined background isdetermined.

Furthermore, the effect, in particular inhibition, of other kinases andthus the selectivity of the compounds according to the invention can bedetermined with the aid of the following assay:

mTOR (Human)

mTOR (human) was incubated with 50 mM HEPES pH 7.5, 1 mM EGTA, 0.01%Tween 20, 2 mg/ml of the substrate, 3 mM MnCl₂ and [γ-³³P-ATP] (specificactivity approximately 500 cpm/pmol, concentration as necessary). Thereaction was initiated by addition of MgATP solution. After incubationat room temperature for 40 minutes, the reaction was stopped by additionof 3% phosphoric acid. 10 μl of the reaction solution were thentransferred dropwise onto a P30 filtermat and washed three times for 5min in 75 mM phosphoric acid and once in methanol, dried and evaluatedby means of liquid scintillation counting.

PI3K p110α/p85α (human), non-radioactive assay

PI3K p110α/p85α (human) was incubated in an assay buffer comprising 10μM phosphatidylinositol 4,5-bisphosphate and MgATP (concentration asnecessary). The reaction was initiated by addition of MgATP solution.After incubation at room temperature for 40 minutes, the reaction wasstopped by addition of a solution consisting of EDTA and biotinylatedphosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer,consisting of a europium-labelled anti-GST monoclonal antibody, aGST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added.The plate was read out via homogeneous time-resolved fluorescence (HTRF)and the corresponding signals were evaluated via the formulaHTRF=10000×(Em665 nm/Em620 nm).

PI3K p110β/p85a (Human), Non-Radioactive Assay

PI3K p110β/p85α (human) was incubated in an assay buffer comprising 10μM phosphatidylinositol 4,5-bisphosphate and MgATP (concentration asnecessary). The reaction was initiated by addition of MgATP solution.After an incubation time of 30 min at room temperature, the reaction wasstopped by addition of a solution consisting of EDTA and biotinylatedphosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer,consisting of a europium-labelled anti-GST monoclonal antibody, aGST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added.The plate was read out via homogeneous time-resolved fluorescence (HTRF)and the corresponding signals were evaluated via the formulaHTRF=10000×(Em665 nm/Em620 nm).

PI3K p110δ/p85α (Human), Non-Radioactive Assay

PI3K p110δ/p85α (human) was incubated in an assay buffer comprising 10μM phosphatidylinositol 4,5-bisphosphate and MgATP (concentration asnecessary). The reaction was initiated by addition of MgATP solution.After an incubation time of 30 min at room temperature, the reaction wasstopped by addition of a solution consisting of EDTA and biotinylatedphosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer,consisting of a europium-labelled anti-GST monoclonal antibody, aGST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added.The plate was read out via homogeneous time-resolved fluorescence (HTRF)and the corresponding signals were evaluated via the formulaHTRF=10000×(Em665 nm/Em620 nm).

PI3K (p120γ) (Human), Non-Radioactive Assay

PI3K (p120γ) (human) was incubated in an assay buffer comprising 10 μMphosphatidylinositol 4,5-bisphosphate and MgATP (concentration asnecessary). The reaction was initiated by addition of MgATP solution.After an incubation time of 30 min at room temperature, the reaction wasstopped by addition of a solution consisting of EDTA and biotinylatedphosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer,consisting of a europium-labelled anti-GST monoclonal antibody, aGST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added.The plate was read out via homogeneous time-resolved fluorescence (HTRF)and the corresponding signals were evaluated via the formulaHTRF=10000×(Em665 nm/Em620 nm).

-   MgATP=magnesium    5′-O-[hydroxy({[(hydroxyphosphinato)oxy]phosphinato}oxy)phosphoryl]adenosine-   MgCl₂=magnesium dichloride-   EGTA=ethylene glycol bis(aminoethyl ether) N,N,N′,N′-tetraacetic    acid-   Tween 20=polysorbate 20    Medicament/Pharmaceutical Composition

The invention also relates to a drug or medicament comprising at leastone compound according to the invention and/or physiologicallyacceptable derivatives, solvates, salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios.

The invention furthermore relates to a pharmaceutical compositioncomprising an effective amount of at least one compound according to theinvention and/or one of its physiologically acceptable derivatives,salts, solvates, tautomers and/or stereoisomers thereof, includingmixtures thereof in all ratios, optionally together with at least onepharmaceutically tolerated adjuvant or optionally an excipient and/oradjuvant.

A “drug”, “medicament” and a “pharmaceutical composition” or“pharmaceutical formulation” is to be taken to mean any compositionwhich can be employed in the prophylaxis, therapy, progress control oraftertreatment of patients who, at least temporarily, exhibit apathogenic modification of the overall condition or the condition ofindividual parts of the patient organism, preferably as a consequence ofcancer, tumours and/or metastases.

In order to increase the protective or therapeutic action of thecompounds according to the invention, pharmaceutically toleratedadjuvants can be added. For the purposes of the invention, any substancewhich facilitates, enhances or modifies an effect with the compounds inaccordance with the invention is an “adjuvant”. Known adjuvants are, forexample, aluminium compounds, such as, for example, aluminium hydroxideor aluminium phosphate, saponins, such as, for example, QS 21, muramyldipeptide or muramyl tripeptide, proteins, such as, for example,gamma-interferon or TNF, MF 59, phosphatdibylcholine, squalene orpolyols. The co-application of egg albumin in complete Freund's adjuvantcan likewise cause increased cell-mediated immunity and thus support theaction of neutralising antibodies formed. Furthermore, DNA, which has animmunostimulatory property, or which encodes a protein with an adjuvanteffect, such as, for example, a cytokine, can be applied in parallel orin a construct.

The introduction of the pharmaceutical composition into a cell ororganism can be carried out in accordance with the invention in anymanner which enables the kinases to be brought into contact with thecompounds present in the composition, as a consequence of which aresponse is induced. The pharmaceutical composition of the presentinvention can be administered orally, transdermally, transmucosally,transurethrally, vaginally, rectally, pulmonarily, enterally and/orparenterally. The type of administration selected depends on theindication, the dose to be administered, individual-specific parameters,etc. In particular, the various types of administration facilitatesite-specific therapy, which minimises side effects and reduces theactive-compound dose. Very particularly preferred injections areintradermal, subcutaneous, intramuscular or intravenous injection. Theadministration can be carried out, for example, with the aid ofso-called vaccination guns or by means of syringes. It is also possibleto provide the substance as an aerosol, which is inhaled by theorganism, preferably a human patient.

The administration forms of the pharmaceutical compositions are preparedusing conventional solid or liquid excipients and/or diluents and theassistants usually employed corresponding to the desired type ofadministration in a suitable dosage and in a manner known per se. Thus,pharmaceutically acceptable excipients known to the person skilled inthe art can basically form part of the pharmaceutical compositionaccording to the invention, where the amount of the excipient materialwhich is combined with the active compound in order to prepare a singledose varies depending on the individual to be treated and the type ofadministration. These pharmaceutically tolerated additions includesalts, buffers, fillers, stabilisers, complexing agents, antioxidants,solvents, binders, lubricants, tablet coatings, flavours, dyes,preservatives, adjusters and the like. Examples of excipients of thistype are water, vegetable oils, benzyl alcohols, alkylene glycol,polyethylene glycol, Kolliphor, glycerol triacetate, gelatine,carbohydrates, such as, for example, lactose or starch,hydroxypropylmethylcellulose (HPMC), magnesium stearate, talc andVaseline. The pharmaceutical formulation can be in the form of a tablet,film tablet, dragee, lozenge, capsule, pill, powder, granules, syrup,juice, drops, solution, dispersion, suspension, suppository, emulsion,implant, cream, gel, ointment, paste, lotion, serum, oil, spray,aerosol, adhesive, plaster or bandage. Oral administration forms whichare prepared are preferably tablets, film tablets, dragees, lozenges,capsules, pills, powders, granules, syrups, juices, drops, solutions,dispersions or suspensions—including as depot form.

Furthermore, parenteral medicament forms, such as, for example,suppositories, suspensions, emulsions, implants or solutions, should beconsidered, preferably oily or aqueous solutions. For topicalapplication, the medicament active compound is formulated in aconventional manner with at least one pharmaceutically acceptablevehicle, such as, for example, microcrystalline cellulose, andoptionally further assistants, such as, for example, moisturisers, togive solid formulations which can be applied to the skin, such as, forexample, creams, gels, ointments, pastes, powders or emulsions, or togive liquid formulations which can be applied to the skin, such as, forexample, solutions, suspensions, lotions, sera, oils, sprays oraerosols. The pharmaceutical composition is preferably in the form of aninjection solution. For the preparation of the injection solution,aqueous media, such as, for example, distilled water or physiologicalsalt solutions, can be used, where the latter include acidic and basicaddition salts. The pharmaceutical composition may also be in the formof a solid composition, for example in the lyophilised state, and isthen prepared before use by addition of a dissolving agent, such as, forexample, distilled water. The person skilled in the art is familiar withthe basic principles of the preparation of lyophilisates.

The concentration of the active compound in the formulation can be 0.1to 100 percent by weight. It is crucial that the pharmaceuticalcomposition comprises, as active compound, an effective amount of thecompound together with the pharmaceutically tolerated assistants. Theterms “effective amount” or “effective dose” are used interchangeablyherein and denote an amount of the pharmaceutical active compound whichhas a prophylactically or therapeutically relevant action on a diseaseor pathological change in cell, tissue, organ or mammal. A “prophylacticaction” prevents the outbreak of a disease or even infection with apathogen after ingress of individual representatives in such a way thatsubsequent propagation is greatly reduced or it is even completelydeactivated. A “prophylactic action” also includes an increase in normalphysiological function. Prophylaxis is advisable, in particular, if anindividual has predispositions for the onset of the above-mentioneddiseases, such as, for example, a family history, a gene defect or arecently survived disease. A “therapeutically relevant action” frees inpart or full from one, more than one or all disease symptoms or resultsin the partial or complete reversal of one, more than one or allphysiological or biochemical parameters which are associated with orcausally involved in the disease or pathological change into the normalstate. Progress control is also taken to be a type of therapeutictreatment if the compounds are administered at certain time intervals,for example in order completely to eliminate the symptoms of a disease.The respective dose or dose range for the administration of thecompounds according to the invention is sufficiently large to achievethe desired prophylactic or therapeutic effect of induction of abiological or medical response. In general, the dose will vary with theage, constitution and gender of the patient, and the severity of thedisease will be taken into account. It goes without saying that thespecific dose, frequency and duration of administration are, inaddition, dependent on a multiplicity of factors, such as, for example,the targeting and binding ability of the compounds, feeding habits ofthe individual to be treated, type of administration, excretion rate andcombination with other drugs. The individual dose can be adjusted bothwith respect to the primary disease and also with respect to theoccurrence of any complications. The precise dose can be established bya person skilled in the art using known means and methods. This teachingof the invention is valid and can be applied without restrictions to thepharmaceutical composition comprising the compounds according toinvention, so long as it appears appropriate.

In an embodiment of the invention, the compounds are administered in adose of 0.01 mg to 1 g per dosage unit, preferably between 1 to 700 mg,particularly preferably 5 to 100 mg. The daily dose is, in particular,between 0.02 and 100 mg/kg of body weight.

Owing to their surprisingly strong and/or selective kinase inhibition,in particular inhibition of ATM kinase, which regulates cellularprocesses via repair of double-strand DNA, the compounds of theinvention can be administered in an advantageously low dose, while theyachieve similar or even superior biological efficacy compared withless-potent or less-selective inhibitors. A reduced dose is typicallyassociated with reduced medical side effects. In addition, highlyselective inhibition is generally also reflected in a reduction inundesired side effects.

All said and further constituents or components of a medicament orpharmaceutical formulation are familiar to the person skilled in the artand may undergo special formulation for the teaching according to theinvention in routine experiments.

Combination Therapy

Medicaments and pharmaceutical compositions which comprise the compoundsaccording to the invention, and the use of these compounds for thetreatment of kinase-mediated disorders are a highly promising approachfor a broad range of therapies, enabling the achievement of direct andimmediate amelioration of symptoms in humans and animals. This isparticularly advantageous for effective combating of severe diseases,such as cancer, either as monotherapy, as outlined above, or incombination with other therapies, such as, for example, chemo- orradiotherapy. The key participation of ATM in DNA repair processes andthe evidence that ATM kinase deficiency allows mammal cells to becomemore radiation sensitive enables therapeutic use of the ATM-specificinhibitors as part of the treatment of, for example, solid cancertumours by irradiation therapy and/or chemotherapy, preferably aimed atDNA double-strand damage.

In order to support the medical action, the pharmaceutical compositionmay correspondingly, in an embodiment of the invention, also compriseone or more further active compounds, for example an anticancer agent,where simultaneous or successive administration is conceivable. Thetherapeutic action of the pharmaceutical composition according to theinvention can consist, for example, in certain anticancer agents havinga better action through the kinase inhibition or the number of sideeffects of these medicaments being reduced by the reduction in the dose.Correspondingly, the compounds according to the invention can beadministered in combination with other active compounds, includinganticancer agents.

In a preferred embodiment of the invention, the pharmaceuticalcomposition according to the invention is combined with or comprises ananticancer agent. Correspondingly, the present invention also relates toa compound according to the invention and/or a pharmaceutically usablederivative, salt, solvate, tautomer or stereoisomer thereof for use inthe treatment of cancer, tumours and/or metastases in combination withat least one anticancer agent.

As used here, the term “anticancer agent” relates to any agent which isadministered to a patient with cancer, tumours and/or metastases for thepurpose of treatment of the cancer.

The anticancer agent is particularly preferably selected from the groupcomprising cytokines, chemokines, pro-apoptotic agents, interferons,radioactive compounds, oestrogen receptor modulators, androgen receptormodulators, retinoid receptor modulators, cytotoxic agents, cytostaticagents, prenyl-protein transferase inhibitors and angiogenesisinhibitors or combinations thereof. It is preferred for the anticanceragent to modify, in particular reduce, nucleic acid and/or proteinmetabolism, cell division, DNA replication, purine, pyrimidine and/oramino acid biosynthesis, gene expression, mRNA processing, proteinsynthesis, apoptosis or combinations thereof.

Anticancer agents which are preferred in accordance with the inventionare those which damage the DNA of tumour cells and thus engage in DNAreplication, DNA transcription or gene expression. The following, inparticular, are suitable for this purpose:

-   -   alkylating agents, such as altretamine, bendamustine, busulfan,        carmustine, chloroambucil, chloromethine, cyclophosphamide,        dacarbazine, ifosfamide, improsulfan tosylate, lomustine,        melphalan, mitobronitol, mitolactol, nimustine, ranimustine,        temozolomide, thiotepa, treosulfan, mechloroetamine, carboquone,        apaziquone, fotemustine, glufosfamide, palifosfamide,        pipobroman, trofosfamide, uramustine,    -   platinum compounds, such as carboplatin, cisplatin, eptaplatin,        miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin,        picoplatin, satraplatin;    -   DDR (DNA damage response) inhibitors, such as topoisomerase        inhibitors, for example etoposide, irinotecan, razoxane,        sobuzoxane, topotecan, camptothecin, doxorubicin, amsacrine;        poly-(ADP-ribose)-polymerase (PARP) inhibitors, for example        talazoparib, olaparib, veliparib, rucaparib, CEP 9722, MK4827,        BGB-290; ATR (ataxia telangiectasia and Rad3 related)        inhibitors, for example VE-822, AZ20, AZD6738    -   DNA-modifying agents, such as amrubicin, bisantrene, decitabine,        mitoxantrone, procarbazine, trabectedine, clofarabine,        amsacrine, brostallicin, pixantrone, laromustine;    -   anticancer antibiotics, such as bleomycin, dactinomycin,        doxorubicin, epirubicin, idarubicin, levamisol, miltefosine,        mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin,        zorubicin, daunurobicin, plicamycin, aclarubicin, peplomycin,        pirarubicin;    -   alpha emitters, such as alpharadin (²²³Ra dichloride, Xofgio),        ²¹¹At, ²¹³Bi, ²²⁵Ac, ²²⁷Th; Particular preference is given to        bleomycin, alpharadin and DDR inhibitors, for example etoposide,        irinotecan, razoxane, sobuzoxane, topotecan, camptothecin,        doxorubicin, amsacrine, talazoparib, olaparib, veliparib,        rucaparib, CEP 9722, MK4827, BGB-290; VE-822, AZ20, AZD6738.

The invention can also be practised as a kit which contains thecompounds according to the invention. The kit consists of separate packs(a) of an effective amount of a compound according to the inventionand/or a physiologically acceptable derivative, salt, tautomer and/orstereoisomer thereof, including mixtures thereof in all ratios, and (b)of an effective amount of a further active compound. The further activecompound is preferably an anticancer agent.

The kit contains suitable containers, such as, for example, boxes orcartons, individual bottles, bags or ampoules. The kit may contain, forexample, separate ampoules, each containing an effective amount of acompound according to the invention and/or pharmaceutically usablederivatives, solvates, salts, tautomers and/or stereoisomers thereof,including mixtures thereof in all ratios, or an effective amount of afurther medicament active compound in dissolved or lyophilised form. Thekit of the invention may also contain an article which contains writteninstructions or points the user towards written instructions whichexplain the handling of the compounds of the invention.

A further embodiment of the present invention relates to the compoundsaccording to the invention in combination with radiotherapy and/or withat least one further active compound, preferably in combination withradiotherapy and/or an anticancer agent. In other words, a furtherembodiment of the present invention relates to the compounds accordingto the invention for use in the treatment of cancer, tumours and/ormetastases in combination with radiotherapy. The present inventionfurthermore relates to a compound according to the invention or apharmaceutically usable derivative, salt, solvate, tautomer and/orstereoisomer thereof for use in the sensitisation of cancer cells to ananticancer agent and/or ionising radiation.

Industrial irradiation methods which are used clinically preferablyinclude photon irradiation (classical, electromagnetic X-ray/gammaradiation), proton irradiation, heavy-ion irradiation (ionised carbon)and neutron irradiation, without being restricted thereto. Theseradiotherapies and other suitable irradiation therapies in the sense ofthe invention are known to the person skilled in the art, such as, forexample, from Herrmann et al. (2006) Klinische Strahlenbiologie[Clinical Radiation Biology], Elsevier Munich, 4th Edition, 67-68; Bhide& Nutting (2010) BMC Medicine 8: 25; Choi & Hung (2010) Current UrologyReports 11(3): 172. As the most frequent application, photon irradiationhas been refined technically by the IMRT (intensity-modulatedradiotherapy) method and by imaging methods (three-dimensional conformalradiotherapy) in irradiation planning and performance for the mostprecise focusing possible. The compounds according to the inventionachieve synergistic effects in existing therapies and irradiationsand/or restore the efficacy of existing therapies and irradiations.Still a further embodiment of the invention relates to the use of atleast one compound and/or pharmaceutically usable derivatives, salts,solvates, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, for the sensitisation of cancer cells to ananticancer agent and/or ionising radiation (radiotherapy), with theproviso that the sensitisation does not take place in vivo on the humanor animal body.

The sensitisation is preferably carried out ex vivo or in vitro byadministering the compounds to cells, cell cultures, tissues or organswhich comprise serine/threonine protein kinases. The ex vivo use isused, in particular, in the case of animal cells which originate from ananimal organism which is affected by a disease which is selected fromthe group of cancer, tumours, metastases and/or angiogenesis disorders.The cells treated ex vivo can either continue to be kept in culture forsubsequent investigations or transferred into an animal, which can bethe host animal or another animal. The ex vivo sensitisation accordingto the invention is particularly advantageous for testing the specificaction of the compounds, so that the in vivo dose can be pre-adjustedcorrespondingly with evaluation of these ex vivo data. As a resultthereof, the therapeutic effect is increased significantly.Alternatively, the invention is also designed for use in vivo andrelates to at least one compound according to the invention and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, for use for thesensitisation of cancer cells to an anticancer agent and/or ionisingradiation.

In summary, it should be noted that the compounds according to theinvention can be used individually and/or in combination with othertreatment measures, such as, for example, surgical interventions,immunotherapy, radiotherapy and/or chemotherapy. The latter relate totargeted therapy with any desired NME (i.e. NCE and/or NBE) asmonotherapy and/or on-target/off-target combination therapy.

All documents cited in the description are hereby intended to beincorporated in their entirety into the disclosure of the presentinvention by way of reference.

It goes without saying that this invention is not restricted to thespecific compounds, pharmaceutical compositions, uses and methods asdescribed herein, since such things can vary. It furthermore goeswithout saying that the terminology used here serves exclusively thepurpose of description of particular embodiments and is not intended torestrict the scope of protection of the invention. As used here in thespecification, including the appended claims, word forms in thesingular, such as, for example, “a” or “the”, include the equivalent inthe plural, so long as the context does not specifically indicateotherwise. For example, the reference to “a compound” includes a singlecompound or a plurality of compounds, which may in turn be identical ordifferent, or the reference to “a method” includes equivalent steps andmethods which are known to the person skilled in the art.

Further Compounds

Besides the above-mentioned compounds of the formula (I), the inventionencompasses compounds of the following general formula (X):

in which

-   R1 denotes A or —(CY₂)_(n)—Ar,-   R2 denotes Y, —(CY₂)_(p)—(C[YR4])_(s)-R5 or -Alk-R5,-   R3 denotes Y, —(CY₂)_(p)—COOY or —(CY₂)_(p)—CO—NYY,-   R4 denotes Y, Hal, —(CY₂)_(n)—NYY, —(CY₂)_(n)—NY—COO—(CY₂)_(n)—SiA₃,    —(CY₂)_(n)—COOY, —CO—NYY, —CO—NY—(CY₂)_(n)—OY, —CO—NY—(CY₂)_(n)—NYY    or —SO₂A,-   R5 denotes —(CY₂)_(p)—Ar or —(CY₂)_(p)-Het¹,-   X denotes CH₂, O, S or a single bond,-   Y denotes H or A,-   A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7,    8, 9 or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms may be    replaced, independently of one another, by Hal,-   Alk denotes alkenylene having 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3    or 4 H atoms may be replaced, independently of one another, by Hal    and/or OY,-   CyA denotes cycloalkyl having 3, 4, 5, 6, 7 or 8 ring C atoms which    is unsubstituted or mono- or polysubstituted, independently of one    another, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY and/or —(CY₂)_(p)—NY—COY,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted, independently of one another, by Hal, A, CN, —NO₂,    —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY    and/or —(CY₂)_(p)—NY—COY,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted, independently of one    another, by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY and/or    —SO₂—Het²,-   Het² denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6    or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or monosubstituted by A,-   HET denotes a 5- or 6-membered aromatic heterocycle having 1, 2 or 3    N atoms and optionally an O atom or S atom, where this heterocycle    is linked to the N atom of the skeleton via a ring C atom and where    this heterocycle may be unsubstituted or substituted by one, two or    three substituents, which are selected, independently of one    another, from the group consisting of: Hal, A, Het², —CN,    —(CY₂)_(p)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,    —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY or —SO₂—Het²; and may be part    of a bicyclic 11- or 12-membered aromatic heterocycle, where this    bicyclic aromatic heterocycle may overall be unsubstituted or    substituted by one, two, three or more substituents, which are    selected, independently of one another, from the group consisting    of: Hal, A, Het², CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—O—(CY₂)_(t)—OY,    —(CY₂)_(p)—O—(CY₂)_(t)—POAA, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY or —SO₂—Het²,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1, 2, 3 or 4,-   n, p, s, independently of one another, denote 0, 1, 2, 3, 4, 5 or 6    and-   t denotes 1, 2, 3, 4, 5 or 6,    and/or pharmaceutically usable salts, solvates, tautomers and    stereoisomers thereof, including mixtures thereof in all ratios,    where, in addition to or in contrast to formula (I), it is not    simultaneously possible for R1 and R3 to denote A and X to denote a    single bond, R2 to denote —(CY₂)_(p)—(C[YR4])_(s)-R5 where p and s=0    and R5 to denote —(CY₂)_(p)-Het¹ where p=0.

The term “Alk” here denotes unbranched or branched alkenylene having 2,3, 4, 5 or 6 C atoms, i.e. C₂₋₆-alkenyls, where, independently of oneanother, 1, 2, 3 or 4 H atoms may be replaced by Hal and/or OY. Alkenylshave at least one C═C double bond, may, in particular, also have twodouble bonds (dienes). Examples of suitable alkenylenes are divalentalkene radicals based on vinyl, allyl, propenyl (—CH₂CH═CH₂; —CH═CH—CH₃;—C(═CH₂)—CH₃), 1-, 2- or 3-butenyl, isobutenyl, 2-methyl-1- or2-butenyl, 3-methyl-1-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl,2,3-dimethyl-1,3-butadienyl, 1-, 2-, 3- or 4-pentenyl and hexenyl, i.e.—CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(═CH₂)—CH₂—, —C(CH₃)═CH—,—CH═C(CH₃)—, —CH═CH—CH₂—CH₂—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—,—CH═C(CH₃)—CH₂—, —CH₂—C(CH₃)═CH—, —CH═CH—CH(CH₃)—, —C(CH₃)═CH—CH₂—,—CH═CH—CH═CH—, —CH═C(CH₃)—CH═CH—, —CH═C(CH₃)—C(CH₃)═CH—,—CH═CH—CH₂—CH₂—CH₂—, —CH₂—CH═CH—CH₂—CH₂—, —CH₂—CH₂—CH═CH—CH₂—,—CH₂—CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH═CH—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH═CH—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH═CH—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH═CH—. “Alk” particularly preferably denotesalkenylene having 2 or 3 C atoms, where 1 or 2 H atoms may be replacedby Hal and/or OH. Very particularly preferred examples thereof areethenylene (—CH═CH—) and propenylene (propenediyl, —CH═CH—CH₂—). It goeswithout saying that the respective meanings of “Alk” are independent ofone another in the radicals of a formula according to the invention.

“Ar” herein denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted, independently of one another, by Hal, A, CN, NO₂,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY. “Ar” particularly preferably denotes phenyl which isunsubstituted or mono- or disubstituted by Hal. It goes without sayingthat the respective meanings of “Ar” are independent of one another inthe radicals of a formula according to the invention. Examples ofsuitable “Ar” are, in particular, (unsubstituted), phenyl, o-, m- orp-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-proylphenyl, o-, m- orp-isoproylphenyl, o-, m- or p-tert-butylphenyl, o-, m- orp-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- orpbromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-hydroxyphenyl, o-,m- or pmethoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl,o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m-or p-aminocarbonylphenyl, o-, m- or pcarboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-cyanophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, piodophenyl, 4-fluoro-3-chlorophenyl,2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl or2,5-dimethyl-4-chlorophenyl.

The definitions and preferred meanings or embodiments mentioned inconnection with the compounds of the formula (I) apply with respect tothe other variables, radicals and substituents.

In compounds of the formula (X), R1 can stand for A, preferablyunsubstituted or substituted C₁-C₃-alkyl, particularly preferablymethyl. Correspondingly, the present invention provides compounds of thefollowing formulae:

Further preferably, R3 stands for Y, i.e. H or A, or Hal. R3particularly preferably stands for A, in particular unbranched orbranched alkyl having 1, 2, or 3 C atoms, where 1, 2, 3, 4, or 5 H atomsmay be replaced, independently of one another, by Hal. R3 particularlypreferably denotes unsubstituted C₁₋₃ alkyl and particularly preferablymethyl.

Correspondingly, the present invention provides compounds of thefollowing formulae:

EXAMPLES

The invention is explained in greater detail below with reference tonon-limiting examples of specific embodiments. The examples (inparticular compound examples) should, in particular, be interpreted insuch a way that they are not restricted to the feature combinationsspecifically illustrated, but instead the illustrative features can inturn be freely combined so long as the object of the invention isachieved.

Analytical Methods

NMR (¹H) was carried out with the following parameters.

Instruments: Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300

Standard conditions (different in individual cases)

Reference: TMS

TD (time domain=number of data points or digital resolution): 65536

Solvent: DMSO-d6

NS(=number of scans): 32

SF (spectrometer frequency): see above

TE (temperature): 297 K

Coupling constants (J) are indicated in hertz (Hz)

HPLC-MS was carried out with the following parameters.

Instruments:

-   -   Shimadzu LCMS-2020,    -   Shimadzu SP-M20A 2010EV    -   Shimadzu UFLC-MS 2010EV        Columns used:    -   Shim-pack VP-ODS,    -   Shim-pack XR-ODS,    -   Kinetex XB-C18 100A,    -   Xbridge BEH C18,    -   Gemini-NX 3u C18 110A    -   ACE UltraCore 2.5 SuperC18        Methods: solvent gradients with    -   A: water+0.1% of formic acid, B: acetonitrile+0.1% of formic        acid;    -   A: water+0.05% of trifluoroacetic acid, B: acetonitrile+0.05% of        trifluoroacetic acid    -   A: water+5 mM ammonium carbonate, B: acetonitrile        Detection wavelength: 220 nm        MS type: API-ES

Description of the Syntheses Example 1: Synthesis of1-(3-fluoro-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 14)

a. Synthesis of 5-bromo-4-methoxy-2-[[(E)-2-nitrovinyl]amino]benzoicAcid

Nitromethane (0.63 ml, 11.7 mmol) was added dropwise at room temperatureto a solution of sodium hydroxide (14.7 g, 368 mmol) in water (33 ml)with stirring. The mixture was subsequently warmed slowly at 45° C. for5 minutes with stirring. The reaction solution was then cooled to roomtemperature, and nitromethane (0.63 ml, 11.7 mmol) was again addeddropwise. The reaction mixture was subsequently stirred for a further 10minutes, during which a clear, reddish solution formed. After briefwarming (5 minutes) at 50° C., the mixture was cooled to roomtemperature and decanted off onto ice (11 g). The aqueous solution wascarefully acidified to pH<2 using conc. hydrochloric acid andsubsequently immediately added to a solution of2-amino-5-bromo-4-methoxybenzoic acid (8.00 g, 32.5 mmol) in water (259ml), acidified using conc. hydrochloric acid (126 ml, 2.75 mol), withstirring. The suspension obtained was stirred overnight and subsequentlyfiltered. The residue was dried at 50°, giving 9.60 g (93%) of5-bromo-4-methoxy-2-[[(E)-2-nitrovinyl]amino]benzoic acid as colourlesssolid.

b. Synthesis of 6-bromo-7-methoxy-3-nitro-1H-quinolin-4-one

5-Bromo-4-methoxy-2-((E)-2-nitrovinylamino)benzoic acid (4.0 g, 12.6mmol) was dissolved in N,N-dimethylformamide (150 ml).1,1′-Carbonyldiimidazole (3.07 g, 18.9 mmol) was subsequently added atroom temperature with stirring. The reaction solution was stirredovernight at room temperature. Acetonitrile (120 ml) was subsequentlyadded. The suspension obtained was cooled and then filtered off. Theyellow residue was washed with diethyl ether and dried overnight at 40°C., giving 3.0 g (80%) of 6-bromo-7-methoxy-3-nitro-1H-quinolin-4-one ascolourless solid.

c. Synthesis of 6-bromo-4-chloro-7-methoxy-3-nitroquinoline

6-Bromo-7-methoxy-3-nitro-1H-quinolin-4-one (2.50 g, 8.36 mmol) wasinitially introduced under a dry nitrogen atmosphere. Phosphorylchloride (20 ml, 215 mmol) and N,N-dimethylformamide (0.13 ml, 1.68mmol) were subsequently added. The reaction solution was heated at 115°C. for 12 hours with stirring. The mixture was subsequently evaporatedin vacuo, and the residue obtained was purified by chromatography onsilica gel (petroleum ether/ethyl acetate=87:13, proportions by volume),giving 2.40 g (90%) of 6-bromo-4-chloro-7-methoxy-3-nitroquinoline ascolourless solid.

d. Synthesis of6-bromo-N-(3-fluoro-2-pyridyl)-7-methoxy-3-nitroquinolin-4-amine

3-Fluoropyridin-2-amine (390 mg, 3.48 mmol), dissolved inN,N-dimethylformamide (10 ml), was initially introduced under a drynitrogen atmosphere. Sodium hydride (630 mg, 26.3 mmol) was subsequentlyadded to the solution, and the mixture was stirred at room temperaturefor a further 5 minutes. 6-Bromo-4-chloro-7-methoxy-3-nitroquinoline(1.00 g, 3.15 mmol) was then added to the reaction mixture, the mixturewas stirred at room temperature for 30 minutes, and the reaction wassubsequently terminated by addition of ice-water (100 ml). The aqueoussolution was extracted three times with 100 ml of ethyl acetate eachtime. The combined organic phases were dried over anhydrous sodiumsulfate, filtered off and evaporated to dryness in vacuo, giving 1.0 g(81%) of6-bromo-N-(3-fluoro-2-pyridyl)-7-methoxy-3-nitroquinolin-4-amine asyellow solid.

e. Synthesis of6-bromo-N-4-(3-fluoro-2-pyridyl)-7-methoxyquinoline-3,4-diamine

6-Bromo-N-(3-fluoro-2-pyridyl)-7-methoxy-3-nitroquinolin-4-amine (1.0 g,2.54 mmol) dissolved in methanol (50 ml) was initially introduced undera nitrogen protective-gas atmosphere. Raney Ni (100 mg, 1.17 mmol) wassubsequently added to the solution, and the reaction mixture was stirredunder a hydrogen atmosphere at atmospheric pressure for 30 minutes.After aeration with nitrogen, the suspension was filtered, and thefiltrate was evaporated to dryness in vacuo, giving 0.8 g (87%) of6-bromo-N-4-(3-fluoro-2-pyridyl)-7-methoxyquinoline-3,4-diamine asyellow solid.

f. Synthesis of8-bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3H-imidazo[4,5-c]quinolin-2-one

6-Bromo-N-4-(3-fluoro-2-pyridyl)-7-methoxyquinoline-3,4-diamine (0.8 g,2.20 mmol) dissolved in tetrahydrofuran were initially introduced.1,1′-Carbonyldiimidazole (1.78 g, 11.0 mmol) and Hünig base (1.42 g,11.0 mmol) were subsequently added. The reaction solution was warmed at40° C. with stirring for 2 hours. The reaction was then terminated byaddition of ice-water (200 ml). The aqueous phase was extracted threetimes with 50 ml of ethyl acetate each time. The combined organic phaseswere dried over anhydrous sodium sulfate, filtered off and evaporated todryness in vacuo, giving 0.8 g (93%) of8-bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3H-imidazo[4,5-c]quinolin-2-oneas pale-yellow solid.

g. Synthesis of8-bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]-quinolin-2-one

8-Bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3H-imidazo[4,5-c]quinolin-2-one(0.8 g, 2.06 mmol), dissolved in N,N-dimethylformamide (10 ml), wasinitially introduced under a dry nitrogen protective atmosphere. Sodiumhydride (412 mg, 17.2 mmol) and methyl iodide (1.46 g, 10.3 mmol) weresubsequently added. The reaction mixture was stirred at room temperaturefor one hour. The reaction was subsequently terminated by addition ofice-water (100 ml). The precipitate obtained was filtered off and driedin vacuo, giving 0.6 g (72%) of8-bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-oneas pale-yellow solid.

h. Synthesis of1-(3-fluoro-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 14)

8-Bromo-1-(3-fluoro-2-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-one(150 mg, 0.37 mmol),1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (93 mg,0.45 mmol), Pd(PPh₃)₄ (43 mg, 0.04 mmol) and potassium carbonate (103mg, 0.75 mmol) in 1,4-dioxane (10 ml) and water (3 ml) were initiallyintroduced under an argon inert-gas atmosphere in a sealed apparatus.The reaction mixture was heated at 80° C. for 2 hours with stirring. Themixture was subsequently cooled to room temperature, and the reactionmixture was evaporated to dryness in vacuo. The residue was pre-purifiedby chromatography on silica gel (ethyl acetate/methanol=10:1,proportions by volume). The eluate was evaporated to dryness, and thecrude product obtained was subjected to final purification by means ofpreparative RP-HPLC (water/acetonitrile). Evaporation of the productfractions gave1-(3-fluoro-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]-quinolin-2-one(60 mg, 40%, Compound Example 14) as colourless solid.

Example 2: Synthesis of7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-1-thiazol-2-ylimidazo-[4,5-c]quinolin-2-one(Compound Example 47)

i. Synthesis of tert-butyl8-bromo-7-methoxy-2-oxo-3H-imidazo[4,5-c]quinoline-1-carboxylate

tert-Butyl N-(3-amino-6-bromo-7-methoxyquinolin-4-yl)carbamate (50.0 mg,0.14 mmol), ditrichloromethyl carbonate (119 mg, 0.40 mmol) andtriethylamine (0.18 ml, 1.29 mmol) were dissolved in dichloromethane (3ml) and stirred at 25° C. for 2 hours. The mixture was evaporated todryness in vacuo, and the residue was purified by chromatography onsilica gel (ethyl acetate:methanol=10:1, proportions by volume), giving50.0 mg (93%) of tert-butyl8-bromo-7-methoxy-2-oxo-3H-imidazo[4,5-c]quinoline-1-carboxylate ascolourless solid.

k. Synthesis of7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-1-thiazol-2-ylimidazo-[4,5-c]-quinolin-2-one

7-Methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-2-one(20 mg, 0.06 mmol), 2-bromo-1,3-thiazole (20 mg, 0.12 mmol), CuI (20.00mg, 0.11 mmol), K₃PO₄ (50 mg, 0.24 mmol) were taken up in toluene (4 ml)under argon in a sealable reaction vessel.(1S,2S)-1-N,2-N-Dimethylcyclohexane-1,2-diamine (30 mg, 0.21 mmol) wassubsequently added at room temperature. The mixture was heated at 100°C. for 18 hours with stirring. The cooled solution was evaporated todryness in vacuo, and the residue was purified by chromatography onsilica gel (water/0.05% of NH₄HCO₃:acetonitrile=10:1), giving 10 mg(43%) of7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-1-thiazol-2-ylimidazo-[4,5-c]quinolin-2-oneas colourless solid.

Example 3: Synthesis of1-[5-(azetidin-3-ylmethoxy)-3-fluoropyridin-2-yl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

i.1-(5-Benzyloxy-3-fluoro-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(1.1 g, 2.15 mmol), MeOH (200 ml), and Pd/C (229 mg, 2.15 mmol) wereinitially introduced in a 500 ml round-necked flask, the flask wasflushed with H₂ and an H₂ atmosphere was maintained. The solution wasstirred at room temperature for 8 hours. Solid was filtered off, and themixture was evaporated in vacuo, giving 740 mg (80%) of1-(3-fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-oneas white solid.

ii.1-(3-Fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(100 mg, 0.23 mmol, 98%), 3-(bromomethyl)azetidine 1-tert-butylcarbamate(80 mg, 0.32 mmol), potassium carbonate (66.2 mg, 0.48 mmol) andN,N-dimethylformamide (10 ml) were initially introduced in a 30 mlreaction vessel. The solution was stirred at 50° C. overnight. Thereaction was then terminated by addition of 10 ml of water. The solutionwas then extracted three times with 10 ml of ethyl acetate each time,the combined organic phases were dried over anhydrous sodium sulfate,filtered off and evaporated in vacuo, giving 160 mg (>100%) of3-[[5-fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-pyridyl]oxymethyl]azetidine1-tert-butylcarbamate as yellow oil.

iii.3-[[5-Fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-pyridyl]oxymethyl]azetidine1-tert-butylcarbamate (160 mg, 0.27 mmol, 99%), dichloromethane (5 ml)and trifluoroacetic acid (1 ml) were initially introduced in a 50 mlround-bottomed flask. The solution was stirred at 25° C. overnight. Thecrude product obtained was purified by means of preparative HPLC, giving30 mg (21%) of1-[5-(azetidin-3-ylmethoxy)-3-fluoropyridin-2-yl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas yellow solid.

Example 4: Synthesis of1-(3-fluoro-5-fluoromethoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one(Compound Example 110)

1-(3-Fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(80 mg, 0.19 mmol, 98%), potassium carbonate (52.4 mg, 0.38 mmol),N,N-dimethylformamide (5 ml) and bromofluoromethane (43.0 mg, 0.36 mmol,95%) were initially introduced in a sealed 30 ml reaction vessel. Thesolution was stirred at room temperature for 2 hours. The reaction wasthen terminated by addition of water. The solution was then extractedthree times with 10 ml of ethyl acetate each time, and the organicphases were combined. The residue was pre-purified on silica gel withEtOAC/MeOH (97/3). The crude product was purified by means ofpreparative HPLC, giving 45 mg (53%) of1-(3-fluoro-5-fluoromethoxypyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas white solid.

Example 5: Synthesis of1-(5-difluoromethoxy-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one(Compound Example 114)

1-(3-Fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(80 mg, 0.18 mmol, 95%), potassium carbonate (52.5 mg, 0.36 mmol, 95%),N,N-dimethylformamide (5 ml) were initially introduced in a sealed 8 mlreaction vessel, the vessel was flushed with chlorodifluoromethane and achlorodifluoromethane atmosphere was maintained at −30° C. The solutionwas stirred at 40° C. for 2 days. The reaction was then terminated byaddition of 20 ml of ice-water. The solution was extracted three timeswith 50 ml of ethyl acetate each time, and the organic phases werecombined. The mixture was washed once with 20 ml of salt solution, driedover anhydrous sodium sulfate and evaporated in vacuo. The crude productwas purified by means of preparative HPLC, giving 27.7 mg (32%) of1-(5-difluoromethoxy-3-fluoropyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas white solid.

Example 6: Synthesis of1-[5-(dimethylphosphinoylmethoxy)-3-fluoropyridin-2-yl]-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

8-(1,3-Dimethylpyrazol-4-yl)-1-(3-fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-one(80 mg, 0.18 mmol, 98%), chloro(dimethylphosphoryl)methane (76.3 mg,0.54 mmol, 90%), potassium carbonate (50 mg, 0.36 mmol) andN,N-dimethylformamide (5 ml) were initially introduced in an 8 mlreaction vessel which had been flushed with argon and kept under argoninert-gas atmosphere. The reaction mixture was heated at 180° C. for 2hours (microwave). The solids obtained were filtered off. The crudeproduct was purified by means of preparative HPLC, giving 11.7 mg (12%)of1-[5-(dimethylphosphinoylmethoxy)-3-fluoropyridin-2-yl]-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas solid.

Example 7: Synthesis of8-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methylsulfonyl-methoxypyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one(Compound Example 201)

i.8-(1,3-Dimethylpyrazol-4-yl)-1-(3-fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-one(80 mg, 0.18 mmol, 98%), N,N-dimethylformamide (5 ml), potassiumcarbonate (50 mg, 0.36 mmol) and chloro(methylsulfanyl)methane (110 mg,1.09 mmol, 95%) were initially introduced in a 25 ml round-bottomedflask. The solution was stirred overnight at 25° C. The reaction wasthen terminated by addition of 50 ml of water. The solution wasextracted four times with 30 ml of ethyl acetate each time, and theorganic phases were combined. The mixture was evaporated in vacuo. Theresidue was pre-purified on silica gel with MeOH:EtOAc (6:94), giving 80mg (85%) of8-(1,3-dimethylpyrazol-4-yl)-1-[3-fluoro-5-(methylsulfanylmethoxy)-2-pyridyl]-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-oneas yellow solid.

ii.8-(1,3-Dimethylpyrazol-4-yl)-1-[3-fluoro-5-(methylsulfanylmethoxy)-2-pyridyl]-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-one(80 mg, 0.15 mmol, 95%), MeOH (5.00 ml) and a solution of potassiumperoxodisulfate (220 mg, 0.77 mmol, 95%) in water (0.5 ml) was initiallyintroduced in a 25 ml round-bottomed flask. The solution was stirred at25° C. for 3 hours. The residue was pre-purified on silica gel withEtOAc:MeOH (70:30), and the crude product was purified by means ofpreparative HPLC, giving 15 mg (18%) of8-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-fluoro-5-methylsulfonylmethoxypyridin-2-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas white solid.

Example 8: Synthesis of1-[3-fluoro-5-(trideuteriomethoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 155)

1-(3-Fluoro-5-hydroxy-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(80 mg, 0.19 mmol, 98%), N,N-dimethylformamide (5.00 ml), potassiumcarbonate (51.7 mg, 0.37 mmol) and iodo(D3)methane (57.1 mg, 0.37 mmol,95%) were initially introduced in a 25 ml round-bottomed flask. Thesolution was stirred at room temperature for 30 minutes. The progress ofthe reaction was followed by means of LCMS (dichloromethane/MeOH=10:1).The reaction was then terminated by addition of 50 ml of ice-water. Thesolution was extracted three times with 20 ml of ethyl acetate eachtime, and the organic phases were combined. The mixture was evaporatedin vacuo, giving 38.5 mg (47%) of1-[3-fluoro-5-(trideuteriomethoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-oneas white solid.

Example 9: Synthesis of1-(3-fluoro-5-piperazin-1-ylpyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one(Compound Example 123)

1-(5-Chloro-3-fluoro-2-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]-quinolin-2-one(100 mg, 0.22 mmol, 95%), piperazine 1-tert-butylcarbamate (128 mg, 0.65mmol, 95%), Pd₂(dba)₃ (21 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol),Cs₂CO₃ (150 mg, 0.46 mmol) and toluene (10 ml) were initially introducedin a sealed 30 ml reaction vessel which had been flushed with argon andkept under argon inert-gas atmosphere. The mixture was stirred at 90° C.overnight and subsequently evaporated in vacuo. The residue was purifiedon silica gel with EtOAc/MeOH (95:5, volume units), giving 120 mg (94%)of4-[5-fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-pyridyl]piperazine1-tert-butylcarbamate as yellow solid.

ii.4-[5-Fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]-3-pyridyl]piperazine1-tert-butylcarbamate (115 mg, 0.18 mmol, 92%), dichloromethane (10 ml)and trifluoroacetic acid (4 ml) were initially introduced in a 25 mlround-bottomed flask. The mixture was stirred for 30 minutes at 0° C. ina water/ice bath and evaporated in vacuo. The crude product was purifiedby means of preparative HPLC, giving 50 mg (55%) of1-(3-fluoro-5-piperazin-1-ylpyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas white solid.

Example 10: Synthesis of5-fluoro-6-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-N-methylnicotinamide(Compound Example 138)

i. A solution of sulfuric acid (2 ml, 98%) in water (2 ml) and5-fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]pyridine-3-nitrile(110 mg, 0.26 mmol) were initially introduced in an 8 ml reactionvessel. The mixture was stirred at 80° C. overnight. Sodium hydroxide (4mol/I) was used to adjust the pH to 8. The mixture was evaporated invacuo, and the residue was purified on silica gel with a 0.5% aqueousNH₄HCO₃ solution and CH₃CN (82/18), giving 70 mg (61%) of5-fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]pyridine-3-carboxylicacid as white solid.

ii.5-Fluoro-6-[7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)-2-oxoimidazo[4,5-c]quinolin-1-yl]pyridine-3-carboxylicacid (65.0 mg, 0.14 mmol), a solution of methylamine (10 mg, 0.32 mmol)in tetrahydrofuran (0.5 ml), triethylamine (44 mg, 0.43 mmol), BOP (64.9mg, 0.15 mmol), and tetrahydrofuran (5 ml) were initially introduced ina sealed 30 ml reaction vessel. The solution was stirred at roomtemperature for 18 hours and evaporated in vacuo, the residue wasdiluted with 10 ml of EtOAc. The mixture was dried over anhydrous sodiumsulfate and evaporated in vacuo. The crude product was purified by meansof preparative HPLC, giving 20 mg (30%) of5-fluoro-6-[7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-N-methylnicotinamideas white solid.

Example 11: Synthesis of1-[3-fluoro-5-(trideuteriomethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 145)

1-(3-Fluoro-5-hydroxy-4-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(145 mg, 0.33 mmol, 97%), CD₃OD (0.3 ml), potassium carbonate (143 mg,1.03 mmol) and N,N-dimethylformamide (3 ml) were initially introduced ina sealed 8 ml reaction vessel. The mixture was stirred at 100° C.overnight. The reaction was then terminated by addition of 10 ml ofwater. The solution was extracted three times with 10 ml of ethylacetate each time. The organic phases were combined, dried overanhydrous sodium sulfate and evaporated in vacuo. The crude product waspurified by means of preparative HPLC, giving 20 mg (14%) of1-[3-fluoro-5-(trideuteriomethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-oneas white solid.

Example 12: Synthesis of1-(3-fluoro-5-methoxypyridin-4-yl)-8-(1-fluoromethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one(Compound Example 140)

1-(3-Fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)imidazo[4,5-c]-quinolin-2-one(60 mg, 0.14 mmol, 97%), potassium carbonate (57.6 mg, 0.42 mmol) andN,N-dimethylformamide (5 ml) were initially introduced in a sealed 30 mlreaction vessel. The mixture was stirred at room temperature for 5minutes and cooled to 0° C. Bromofluoromethane (165 mg, 1.39 mmol, 95%)was added, the mixture was warmed to room temperature and stirred for afurther hour. The reaction was then terminated by addition of 50 mL ofwater. The solution was extracted three times with 30 mL of ethylacetate each time, the organic phases were combined and evaporated invacuo. The crude product was purified by means of preparative HPLC,giving 5 mg (8%) of1-(3-fluoro-5-methoxypyridin-4-yl)-8-(1-fluoromethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-oneas white solid.

Example 13: Synthesis of1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 4)

a. Synthesis of6-bromo-N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitroquinolin-4-amine

3-Fluoro-5-methoxypyridin-4-amine (447 mg, 3.02 mmol), dissolved inN,N-dimethylformamide (5 ml), were initially introduced under a drynitrogen atmosphere. Sodium hydride (504 mg, 12.6 mmol, 60%) wassubsequently added to the solution, and the mixture was stirred at roomtemperature for a further 5 minutes.6-Bromo-4-chloro-7-methoxy-3-nitroquinoline (800 mg, 2.52 mmol) was thenadded to the reaction mixture, the mixture was stirred at roomtemperature for 15 minutes, and the reaction was subsequently terminatedby addition of ice-water (100 ml). The deposited precipitate wasfiltered off, washed with ice-water and dried, giving 1.0 g (94%) of6-bromo-N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitroquinolin-4-amineas yellow solid.

b. Synthesis of6-bromo-N4-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxyquinoline-3,4-diamine

6-Bromo-N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitroquinolin-4-amine(990 mg, 2.20 mmol), dissolved in methanol (100 ml), was initiallyintroduced under a nitrogen protective-gas atmosphere. Raney Ni (100 mg,1.17 mmol) was subsequently added, and the reaction mixture was stirredunder a hydrogen atmosphere at atmospheric pressure for 30 minutes.After aeration with nitrogen, the suspension was filtered, and thefiltrate was evaporated to dryness in vacuo. The residue wascrystallised from ethyl acetate/petroleum ether, giving 0.86 g (99%) of6-bromo-N4-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxyquinoline-3,4-diamineas yellow solid.

c. Synthesis of8-bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3H-imidazo[4,5-c]-quinolin-2-one

6-Bromo-N4-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxyquinoline-3,4-diamine(0.85 g, 2.20 mmol), dissolved in tetrahydrofuran (20 ml), wereinitially introduced. 1,1′-Carbonyldiimidazole (1.84 g, 11.3 mmol) andHünig base (1.46 g, 11.3 mmol) were subsequently added. The reactionsolution was warmed at 40° C. for 16 hours with stirring. The reactionwas then terminated by addition of ice-water (200 mL). The depositedprecipitate was filtered off, washed with ice-water and dried, giving0.87 g (94%) of8-bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3H-imidazo[4,5-c]quinolin-2-oneas pale-yellow solid.

d. Synthesis of8-bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methylimidazo[4,5-c]quinolin-2-one

8-Bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3H-imidazo[4,5-c]quinolin-2-one(0.86 g, 1.94 mmol), dissolved in N,N-dimethylformamide (5 ml), wasinitially introduced under a dry nitrogen protective atmosphere. Sodiumhydride (388 mg, 9.71 mmol, 60%) and methyl iodide (2.76 g, 19.4 mmol)were subsequently added. The reaction mixture was stirred at roomtemperature for 10 minutes. The reaction was subsequently terminated byaddition of ice-water (100 mL). The precipitate obtained was filteredoff and dried in vacuo, giving 0.70 g (80%) of8-bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-oneas pale-yellow solid.

e. Synthesis of1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(Compound Example 4)

8-Bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methylimidazo-[4,5-c]quinolin-2-one(150 mg, 0.33 mmol),1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88.4 mg,0.44 mmol), Pd(PPh₃)₄ (76.6 mg, 0.07 mmol) and potassium carbonate (91.6mg, 0.66 mmol) in 1,4-dioxane (15 ml) and water (5 ml) were initiallyintroduced under an argon inert-gas atmosphere in a sealed apparatus.The reaction mixture was heated at 80° C. for 2 hours with stirring. Thereaction mixture was subsequently cooled to room temperature andevaporated to dryness in vacuo. The residue was pre-purified bychromatography on silica gel (ethyl acetate/methanol=97:3, proportionsby volume). The eluent was evaporated to dryness, and the crude productobtained was subjected to final purification by means of preparativeRP-HPLC (water/acetonitrile). Evaporation of the product fractions gave1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo[4,5-c]quinolin-2-one(70 mg, 47%, Compound Example 4) as colourless solid.

The abbreviations used above, which are usual in the specialist area,have the following meanings: MeOH: methanol; Pd(PPh₃)₄:tetrakis(triphenylphosphine)palladium; EtOAc: ethyl acetate; BOP:benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate;Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium

Example 14

Compound examples prepared correspondingly or analogously to EXAMPLES 1to 13 are shown in Table 2 below. The amine derivatives, boronic acidesters or analogues used are summarised in Schema 4 below.

TABLE 2 IC₅₀ IC₅₀ (ATM) Ex. Structural formula Name (pCHK2) [μM] 1

1-(3,5-Difluoropyridin-2-yl)- 7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.001 MS: 423 (M + H⁺) 1H NMR (400 MHz, DMSO-d6 ppm): 8.915 (s, 1H),8.855-8.849 (d, J = 2.4 Hz, 1H), 8.544-8.495 (m, 1H), 8.016 (s, 1H),7.538 (s, 1H), 7.339 (s, 1H), 6.944 (s, 1H), 4.005 (s, 3H), 3.864 (s,3H), 3.597 (s, 3H) 2

1-(3,5-Difluoropyridin-4-yl)- 7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.001 MS:409 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 13.036 (s, 1H), 9.050 (s, 2H),8.944 (s, 1H), 7.992 (s, 1H), 7.563 (s, 1H), 7.440 (s, 1H), 7.281 (s,1H), 4.012 (s, 3H), 3.613 (s, 3H) 3

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 390 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 13.03 (s, 1H), 8.80 (s,1H), 8.13 (s, 1H), 7.96 (br, 1H), 7.45 (d, 3H), 3.97 (m, 6H), 3.53 (s,3H), 1.94 (s, 3H) 4

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3- methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one +++ <0.001 MS: 449 (M + H⁺) 1H NMR (400 MHz, DMSO,ppm): 8.912 (s, 1H), 8.707-8.681 (m, 2H), 7.822 (s, 1H), 7.527 (s, 1H),6.985 (s, 1H), 3.927 (s, 3H), 3.861 (s, 3H), 3.766 (s, 3H), 3.595 (s,3H), 1.744 (s, 3H) 5

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one+++ <0.001 MS: 404 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.80 (s, 1H),8.13 (s, 1H), 8.00 (s, 1H), 7.41 (m, 3H), 3.97 (m, 6H), 3.87 (d, 3H),3.54 (s, 3H), 1.94 (s, 3H) 6

1-(3,5-Difluoropyridin-2-yl)- 7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.001 MS:410 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 12.95 (br, 1H), 8.86 (d, 2H),8.51 (m, 1H), 7.71 (s, 2H), 7.52 (s, 1H), 6.96 (s, 1H), 3.99 (s, 3H),3.29 (s, 3H) 7

1-(3-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.001 MS:391 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 13.007 (s, 1H), 8.907 (s, 1H),8.727 (s, 1H), 8.305-8.241 (m, 1H), 7.981-7.939 (m, 2H), 7.526 (s, 1H),7.321 (s, 1H), 6.934 (s, 1H), 3.997 (s, 3H), 3.597 (s, 3H) 8

1-(3-Fluoro-5-methylpyridin- 4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 13.035 (s, 1H), 8.930 (s,1H), 8.901 (s, 1H), 8.805 (s, 1H), 7.920 (s, 1H), 7.544 (s, 1H), 7.271(s, 1H), 7.030 (s, 1H), 3.999 (s, 3H), 3.615 (s, 3H), 2.220 (s, 3H) 9

1-(3-Fluoropyridin-4-yl)-7- methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.001 MS:391 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 13.023 (s, 1H), 9.075 (s, 1H),8.908 (s, 1H), 8.838-8.825 (d, J = 5.2 Hz, 1H), 7.997-7.940 (m, 2H),7.537 (s, 1H), 7.337 (s, 1H), 7.195 (s, 1H), 4.000 (s, 3H), 3.589 (s,3H) 10

1,8-Bis-(1,3-dimethyl-1H- pyrazol-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo- [4,5-c]quinolin-2-one +++ <0.001 MS: 418 (M +H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.82 (s, 1H), 8.08 (s, 1H), 7.86 (s,1H), 7.48 (s, 1H), 7.35 (s, 1H), 3.92 (d, 3H), 3.87 (s, 3H), 3.78 (s,3H), 3.54 (s, 3H), 1.90 (d, 6H) 11

1-(3,5-Difluoropyridin-2-yl)- 8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 437 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.829 (s, 1H),8.605-8.599 (d, J = 2.4 Hz, 1H), 8.133-8.085 (m, 1H), 7.700 (s, 1H),7.499 (s, 1H), 6.874 (s, 1H), 3.985 (s, 3H), 3.852 (s, 3H), 3.680 (s,3H), 1.948 (s, 3H) 12

1-(3-Ethyl-5-fluoropyridin-4- yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one+++ <0.001 MS: 433 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.935 (s, 2H),8.853 (s, 1H), 7.986 (s, 1H), 7.545 (s, 1H), 7.062 (s, 1H), 6.960 (s,1H), 3.994 (s, 3H), 3.844 (s, 3H), 3.618 (s, 3H), 2.672-2.600 (m, 2H),1.069-1.002 (m, 3H) 13

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-fluoro-5- methoxypyridin-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++ <0.001MS: 449 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.896 (s, 1H), 8.789 (s,1H), 8.744 (s, 1H), 8.024 (s, 1H), 7.527 (s, 1H), 7.206 (s, 1H), 7.158(s, 1H), 4.175-4.120 (m, 2H), 4.002 (s, 3H), 3.877 (s, 3H), 3.333 (s,3H), 1.390-1.354 (m, 3H) 14

1-(3-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.908 (s, 1H),8.719-8.708 (m, 1H), 8.295-8.271 (m, 1H), 7.977- 7.930 (m, 2H), 7.525(s, 1H), 7.195-7.194 (s, 1H), 6.896 (s, 1H), 4.033 (s, 3H), 3.994 (s,3H), 3.595 (s, 3H) 15

1-(3-Fluoro-5- methoxypyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 435 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.896 (s, 1H),8.780 (s, 1H), 8.739 (s, 1H), 8.007 (s, 1H), 7.528 (s, 1H), 7.176-7.149(m, 2H), 3.998 (s, 3H), 3.870 (s, 6H), 3.596 (s, 3H) 16

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoropyridin-2-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 419 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.93 (s, 1H), 8.63-8.62(d, J = 4.8 Hz, 1H), 8.25-8.20 (m, 1H), 7.89-7.85 (m, 1H), 7.77 (s, 1H),7.53 (s, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.59 (s, 3H),1.75 (s, 3H) 17

7-Methoxy-3-methyl-1-(1- methyl-1H-pyrazol-4-yl)-8-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 375 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 13.009 (s, 1H), 8.802 (s,1H), 8.239 (s, 1H), 7.818 (s, 1H), 7.729 (s, 2H), 7.476 (m, 2H), 4.034(s, 3H), 3.987 (s, 3H), 3.532 (s, 3H) 18

1-(3-Fluoro-5-methylpyridin- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 419 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.930 (s, 1H), 8.895(s, 1H), 8.800 (s, 1H), 7.981 (s, 1H), 7.544 (s, 1H), 7.109 (s, 1H),6.999 (s, 1H), 3.996 (s, 3H), 3.844 (s, 3H), 3.613 (s, 3H), 2.215 (s,3H) 19

7-Methoxy-3-methyl-1-(3- methylpyridin-4-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.01 MS:387 (M + H⁺) 1H NMR (400 Hz, DMSO, ppm): 2.141 (s, 3H), 3.596 (s, 3H),3.991 (s, 3H), 6.970 (s, 1H), 7.202 (s, 1H), 7.517 (s, 1H), 7.682-7.695(d, J = 5.2 Hz, 1H), 7.883 (s, 1H), 8.777-8.789 (d, J = 4.8 Hz, 1H),8.900 (s, 2H), 13.016 (s, 1H) 20

1-(3-Fluoro-5-methylpyridin- 2-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 405 (M + H⁺) 1H NMR (400 MHz, MeOD, ppm): 8.747 (s, 1H), 8.514 (s,1H), 7.941-7.914 (d, J = 10.8, 2H), 7.422 (s, 2H), 6.947 (s, 1H), 4.019(s, 3H), 3.654 (s, 3H), 2.618 (s, 3H) 21

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +++<0.001 MS: 418 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.81 (s, 1H), 8.14(s, 1H), 8.03 (s, 1H), 7.78-7.38 (m, 3H), 4.16 (m, 2H), 3.99 (d, 6H),3.55 (s, 3H), 1.95 (s, 3H), 1.40 (m, 3H) 22

1-(3,5-Difluoropyridin-4-yl)- 7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.001 MS: 423 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.050 (s, 2H),8.499 (s., 1H), 8.030 (s, 1H), 7.562 (s, 1H), 7.312- 7.254 (d, J = 23.2,2H), 4.010 (s, 3H), 3.854 (s, 3H), 3.611 (s, 3H). 23

7-Methoxy-3-methyl-1,8-bis- (1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one +++ <0.01 MS: 390 (M + H⁺) 1HNMR (300 MHz, DMSO, ppm): 8.798 (s, 1H), 8.241 (s, 1H), 8.005 (s, 1H),7.811 (s, 1H), 7.471- 7.462 (d, J = 2.7 Hz, 2H), 7.348 (s, 1H), 4.037(s, 3H), 3.984 (s, 3H), 3.874 (s, 3H), 3.525 (s, 3H) 24

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-fluoropyridin-2-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 419 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.907 (s, 1H), 8.732-8.721(m, 1H), 8.300-8.252 (m, 1H), 7.997- 7.936 (m, 2H), 7.524 (s, 1H), 7.226(s, 1H), 6.907 (s, 1H), 4.165-40125 (m, 2H), 3.998 (s, 3H), 3.596 (s,3H), 1.387-1.350 (m, 3H) 25

1-(3-Ethyl-5-fluoropyridin-4- yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.001 MS: 447 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.934 (s, 2H),8.860 (s, 1H), 8.001 (s, 1H), 7.544 (s, 1H), 7.098 (s, 1H), 6.973 (s,1H), 4.165-4.111 (m, 2H), 3.999 (s, 3H), 3.619 (s, 3H), 2.678-2.605 (m,2H), 1.384- 1.348 (m, 3H), 1.045-1.007 (m, 3H) 26

1-(3,5-Difluoropyridin-4-yl)- 8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 437 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 9.162 (s, 1H), 9.078 (s,2H), 8.101 (s., 1H), 7.618 (s, 1H), 7.380 (s, 2H), 4.192-4.120 (m, 2H),4.062 (s, 3H), 3.631 (s, 3H), 1.398-1.351 (m, 3H). 27

1-(3-Fluoro-5-methylpyridin- 2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +++<0.001 MS: 419 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.896 (s, 1H),8.577 (s, 1H), 8.144-8.118 (d, J = 10.4, 1H), 7.948 (s, 1H), 7.517 (s,1H), 7.218 (s, 1H), 6.857 (s, 1H), 3.992 (s, 3H), 3.852 (s, 3H), 3.588(s, 3H), 2.672 (s, 3H) 28

7-Methoxy-1-(3-methoxy- pyridin-4-yl)-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 417 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 8.855 (m, 2H), 8.581(s, 1H), 7.973 (s., 1H), 7.758 (s, 1H), 7.492 (s, 1H), 7.093 (s, 2H),4.021 (s, 3H), 3.843 (m, 3H), 3.570 (s, 3H), 3.319 (s, 3H) 29

1-(3-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(5-methyl-1H-pyrazol-3-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.936 (s, 1H), 8.628(s, 1H), 8.263-8.239 (m, 1H), 7.891-7.841 (m, 2H), 7.541 (s, 1H), 7.376(s, 1H), 6.319 (s, 1H), 5.980 (s, 1H), 4.016 (s, 3H), 3.595 (s, 3H),2.220 (s, 3H) 30

7-Methoxy-3-methyl-1-(2- methylthiazol-4-yl)-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.01 MS:393 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 12.96 (br, 1H), 8.84 (s, 1H),8.00 (s, 1H), 7.73 (s, 2H), 7.48 (s, 1H), 7.15 (s, 1H), 3.99 (s, 3H),3.55 (s, 3H), 2.79 (s, 3H) 31

1-(5-Fluoropyrimidin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1H,2H,3H-imidazo[4,5-c] quinolin-2-onehydrochloride +++ <0.01 MS: 406 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm):9.43-9.31 (m, 3H), 8.14 (s, 1H), 7.75 (s, 1H), 7.56 (d, 2H), 4.08 (s,3H), 3.88 (s, 3H), 3.62 (s, 3H) 32

7-Methoxy-1-(3-methoxy- pyridin-4-yl)-3-methyl-8- (1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one +++ <0.01 MS: 403 (M + H⁺) 1H NMR(300 MHz, DMSO, ppm): 13.016 (s, 1H), 8.856 (s, 2H), 8.584 (s., 1H),7.908 (s, 1H), 7.766 (s, 1H), 7.492 (s, 1H), 7.255 (s, 1H), 7.119 (s,1H), 3.986 (s, 3H), 3.801 (s, 3H), 3.571 (s, 3H) 33

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-fluoropyridin-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.001MS: 419 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.076 (s, 1H), 8.908 (s,1H), 8.842-8.829 (d, J = 5.2 Hz, 1H), 8.009 (s, 1H), 7.997-7.969 (m,1H), 7.535 (s, 1H), 7.217 (s, 1H), 7.175 (s, 1H), 4.166-4.112 (m, 2H),4.000 (s, 3H), 3.587 (s, 3H), 1.383-1.347 (m, 3H) 34

8-(1-Ethyl-1H-pyrazol-4-yl)- 7-methoxy-3-methyl-1-(3-methylpyridin-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.01MS: 415 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 1.349-1.386 (t, J = 7.4Hz, 3H), 2.139 (s, 3H), 3.597 (s, 3H), 3.994 (s, 3H), 4.1-4.2 (m, 2H),6.949 (s, 1H), 7.066 (s, 1H), 7.517 (s, 1H), 7.682-7.695 (d, J = 5.2 Hz,1H), 7.968 (s, 1H), 8.780-8.793 (d, J = 5.2 Hz, 1H), 8.900 (s, 2H) 35

1-(3-Fluoropyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.073-9.070 (d, J =1.2 Hz, 1H), 8.901 (s, 1H), 8.838-8.825 (d, J = 5.2 Hz, 1H), 7.993-7.964(m, 2H), 7.532 (s, 1H), 7.185 (s, 1H), 7.164 (s, 1H), 3.995 (s, 3H),3.847 (s, 3H), 3.583 (s, 3H) 36

1-(5-Fluoropyrimidin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 406 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.33 (s, 2H), 8.89(s, 1H), 8.08 (s, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 6.92 (s, 1H), 4.11(s, 3H), 3.99 (s, 3H), 3.57 (s, 3H) 37

7-Methoxy-3-methyl-8-(1H- pyrazol-4-yl)-1-[1- (tetrahydropyran-4-yl)-1H-pyrazol-4-yl]-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.01 MS:446 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 12.98 (br, 1H), 8.79 (s, 1H),8.35 (s, 1H), 7.84 (s, 1H), 7.69 (s, 2H), 7.44 (d, 2H), 4.58 (m, 1H),4.00 (m, 5H), 3.52 (m, 5H), 2.07 (m, 4H) 38

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-fluoro-5-methylpyridin-4-yl)-7-methoxy-3-methyl- 1,3-dihydroimidazo[4,5-c] quinolin-2-one ++<0.001 MS: 433 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.929 (s, 1H),8.904 (s, 1H), 8.806 (s, 1H), 7.993 (s, 1H), 7.543 (s, 1H), 7.144 (s,1H), 7.010 (s, 1H), 4.165-4.111 (m, 2H), 4.000 (s, 3H), 3.614 (s, 3H),2.218 (s, 3H), 1.384-1.348 (m, 3H) 39

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5-methyl-pyridin-4-yl)-7-methoxy-3- methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.001 MS: 433 (M + H⁺) 1H NMR (400 MHz, DMSO,ppm): 8.948 (s, 1H), 8.833 (s, 1H), 8.732 (s, 1H), 7.824 (s, 1H), 7.545(s, 1H), 6.874 (s, 1H), 3.929 (s, 3H), 3.759 (s, 3H), 3.611 (s, 3H),2.189 (s, 3H), 1.702 (s, 3H) 40

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++<0.01 MS: 401 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 2.128 (s, 3H), 3.589(s, 3H), 3.833 (s, 3H), 3.982 (s, 3H), 6.933 (s, 1H), 7.018 (s, 1H),7.511 (s, 1H), 7.665-7.678 (d, J = 5.2 Hz, 1H), 7.953 (s, 1H),8.764-8.777 (d, J = 5.2 Hz, 1H), 8.886-8.893 (d, J = 2.8 Hz, 2H). 41

7-Methoxy-3-methyl-1-(2- methyl-2H-pyrazol-3-yl)-8-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++ <0.01 MS:376 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.77 (s, 1H), 7.85 (s, 1H),7.73 (s, 2H), 7.50 (s, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 6.04 (s, 1H),3.99 (s, 3H), 3.73 (s, 3H), 3.62 (s, 3H) 42

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO,ppm): 8.85 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.52 (s,1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.91 (s, 3H), 3.54 (s, 3H), 1.93 (s,3H) 43

7-Methoxy-3-methyl-1-(3- methyl-1H-pyrazol-4-yl)-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.001 MS: 390 (M + H⁺) 1H NMR 1H NMR (400 MHz, DMSO): 13.21 (s, 1H),8.80 (s, 1H), 7.98 (d, J = 25.3 Hz, 2H), 7.47 (s, 1H), 7.36 (s, 1H),7.31 (s, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.54 (s, 3H), 2.05 (s, 3H). 44

5-Fluoro-4-[7-methoxy-3- methyl-8-(1-methyl-1H- pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl]nicotinonitrile ++ <0.01 MS: 430(M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.399 (s, 1H), 9.346 (s, 1H),8.968 (s, 1H), 8.036 (s, 1H), 7.578 (s, 1H), 7.404 (s, 1H), 7.215 (s,1H), 4.020 (s, 3H), 3.851 (s, 3H), 3.636 (s, 3H) 45

4-[7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]pyridine 2-carbonitrile ++<0.05 MS: 412 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.099 (s, 1H), 8.913(s, 1H), 8.497 (s, 1H), 8.106 (s, 1H), 8.097 (s, 1H), 7.549 (s, 1 H),7.332 (s, 1H), 7.269 (s, 1H), 4.007 (s, 3H), 3.857 (s, 3H), 3.574 (s,3H) 46

4-[7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]- nicotinonitrile ++ <0.05MS: 412 (M + H⁺) 1H NMR (400 MHz, CDCl3, ppm): 9.219 (s, 1H), 9.122 (s,1H), 8.718 (s, 1H), 7.767 (s, 1H), 7.689 (s, 2H), 7.300 (s, 1H), 7.140(s, 1H), 4.071 (s, 3H), 3.924 (s, 3H), 3.686 (s, 3H) 47

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-thiazol-2-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.01 MS: 393(M + H⁺) 1H NMR (400 HMz, DMSO, ppm): 8.82 (s, 1H), 8.04 (s, 2H), 7.98(s, 1H), 7.60 (s, 1H), 7.40 (d, 2H), 3.94 (s, 3H), 3.81 (s, 3H), 3.50(s, 3H) 48

6-[7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]- nicotinonitrile ++ <0.01MS: 412 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 9.308 (s, 1H), 8.909 (s,1H), 8.744 (m, 1H), 8.090 (m, 1H), 8.009 (s, 1H), 7.524 (s, 1H), 7.402(s, 1H), 7.242 (s, 1H), 4.003 (s, 3H), 3.865 (s, 3H), 3.576 (s, 3H) 49

7-Methoxy-3-methyl-1-(2- methyl-2H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 390 (M + H⁺) 1H NMR (300 MHz, MeOD, ppm): 8.79 (s, 1H), 7.90(m, 2H), 7.51 (s, 2H), 7.04 (s, 1H), 6.72 (s, 1H), 4.06 (s, 3H), 3.92(s, 3H), 3.73 (s, 3H), 3.66 (s, 3H) 50

1-(5-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 405 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.916 (m, 2H), 8.240(m, 1H), 7.963 (m, 2H), 7.515 (s, 1H), 7.258 (m, 1H), 6.993 (s, 1H),4.174 (s, 3H), 3.854 (s, 3H), 3.523 (s, 3H) 51

1-(3-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4- yl)-1,3-dihydroimidazo- [4,5-c]quinolin-2-one++ <0.01 MS: 406 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.964 (s, 1H),8.643 (s, 1H), 8.424 (s, 1H), 8.287-8.239 (m, 1H), 7.939-7.907 (m, 1H),7.769 (s, 1H), 7.593 (s, 1H), 4.057 (s, 6H), 3.606 (s, 3H) 52

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-pyrimidin-2-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.01 MS:388 (M + H⁺) 1H NMR (300 MHz, DMSO): 3.57 (s, 3H), 3.85 (s, 3H), 3.99(s, 3H), 6.83 (s, 1H), 7.26 (s, 1H), 7.51 (s, 1H), 7.93 (t, J = 4.8,1H), 7.98 (s, 1H), 8.89 (s, 1H), 9.23 (d, J = 4.8, 2H). 53

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.01MS: 376 (M + H⁺) 1H NMR (400 MHz, DMSO): 8.80 (s, 1H), 8.03 (d, J = 20.4Hz, 2H), 7.46 (s, 1H), 7.39 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H), 3.85(s, 3H), 3.53 (s, 3H). 54

1-(3-Ethyl-5-methylpyridin- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 429 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.918 (s, 1H), 8.751(s, 1H), 8.714 (s, 1H), 7.952 (s, 1H), 7.514 (s, 1H), 6.963 (s, 1H),6.831 (s, 1H), 3.982 (s, 3H), 3.833 (s, 3H), 3.681 (s, 3H), 2.469-2.329(m, 3H), 1.977 (s, 3H), 0.966-0.928 (m, 3H) 55

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-[1-(tetrahydropyran-4-yl)- 1H-pyrazol-4-yl]-1,3- dihydroimidazo[4,5-c]-quinolin-2-one ++ <0.01 MS: 460 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm):8.80 (s, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.40 (m, 3H),4.60 (m, 1H), 3.97 (m, 5H), 3.84 (s, 3H), 3.53 (m, 5H), 2.07 (m, 4H) 56

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-pyridin-2-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.01 MS: 387(M + H⁺) 1H NMR (DMSO, 400 MHz, ppm): 8.874 (s, 1H), 8.816-8.832 (m,1H), 8.2-8.3 (t, 1H), 7.964 (s, 1H), 7.822-7.842 (d, J = 8.0 Hz, 1H),7.758-7.789 (m, 1H), 7.494 (s, 1H), 7.160 (s, 1H), 6.984 (s, 1H), 3.986(s, 3H), 3.842 (s, 3H), 3.575 (s, 3H) 57

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-pyrimidin-5-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.05 MS:388 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 9.512 (s, 1H), 9.241 (s, 2H),8.906 (s, 1H), 7.991 (s, 1H), 7.541 (s, 1H), 7.247 (s, 1H), 7.134 (s,1H), 4.035-4.004 (s, 3H), 3.884-3.857 (s, 3H), 3.590 (s, 3H) 58

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-pyridin-4-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.01 MS: 387(M + H⁺) 1H NMR (300 MHZ, DMSO): 3.57 (s, 3H), 3.84 (s, 3H), 3.99 (s,3H), 7.11 (s, 1H), 7.20 (s, 1H), 7.50 (s, 1H), 7.75 (d, J = 6.0 Hz, 2H),8.00 (s, 1H), 8.90 (s, 1H), 8.99 (d, J = 6.0 Hz, 2H) 59

7-Methoxy-3-methyl-1-(1- methyl-1H-imidazol-4-yl)-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +<0.01 MS: 390 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.79 (s, 1H), 7.96(1d, 2H), 7.58 (s, 1H), 7.45 (s, 1H), 7.39 (d, 2H), 4.00 (s, 3H), 3.88(m, 6H), 3.53 (s, 3H) 60

1-(3-Chloropyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one +<0.01 MS: 421 (M + H⁺) 1H NMR (300 MHz, DMSO, ppm): 9.43 (s, 1H), 9.24(s, 1H), 9.03 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 5.1 Hz, 2H), 7.98 (s,1H), 7.13 (s, 1H), 7.06 (s, 1H), 4.07 (s, 3H), 3.87 (s, 3H), 3.67 (s,3H) 61

1-(3-Ethyl-5-methylpyridin- 4-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +<0.01 MS: 443 (M + H⁺) 1H NMR (400 MHz, DMSO, ppm): 8.918 (s, 1H), 8.760(s, 1H), 8.723 (s, 1H), 7.963 (s, 1H), 7.516 (s, 1H), 7.009 (s, 1H),6.847 (s, 1H), 4.156-4.102 (m, 2H), 3.989 (s, 3H), 3.622 (s, 3H),2.514-2.458 (m, 2H), 2.004 (s, 3H), 1.382-1.345 (m, 3H), 0.973- 0.936(m, 3H) 62

8-(1-Ethyl-1H-pyrazol-4-yl)- 7-methoxy-3-methyl-1-pyridin-4-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one + <0.01 MS: 401(M + H⁺) 1H NMR (400 MHZ, DMSO, ppm): 1.35 (t, J = 7.6 Hz, 3H), 3.56 (s,3H), 3.98 (s, 3H), 4.12 (q, J = 7.6, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.51(s, 1H), 7.74 (d, J = 6 Hz, 2H), 7.98 (s, 1H), 8.87 (s, 1H), 8.95 (br,2H) 63

1-(3-Fluoro-5-methylpyridin- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 420 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 8.97 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.42 (s, 1H)7.91 (s, 1H), 7.60 (s, 1H), 4.10 (s, 6H), 3.61 (s, 3H), 2.19 (s, 3H) 64

1-(3-Fluoropyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol-4- yl)-1,3-dihydroimidazo- [4,5-c]quinolin-2-one++ <0.01 MS: 406 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 9.01 (s, 1H),8.94 (s, 1H), 8.78-8.77 (m, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.94-7.92(m, 1H), 7.58 (s, 1H), 4.05 (s, 6H), 3.58 (s, 3H) 65

8-(3-Amino-1H-pyrazol-5- yl)-1-(3-fluoro-2-pyridyl)-7-methoxy-3-methyl-imidazo- [4,5-c]quinolin-2-one ++ <0.001 MS: 406 (M +H⁺) 1H NMR (400 MHz, DMSO) ppm = 11.3 (s, 1H), 8.87 (s, 1H), 8.60-8.59(m, 1H), 8.17-8.10 (m, 1H), 7.86-7.80 (m, 1H), 7.52 (s, 1H), 7.16 (s,1H), 5.50 (s, 1H), 4.40 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H). 66

1-[3-Fluoro-5-(2-methoxy- ethoxy)-2-pyridyl]-7- methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo- [4,5-c]quinolin-2-one +++ <0.001 MS: 479(M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.90 (s, 1H), 8.48 (s, 1H),8.02-7.97 (m, 2H), 7.52 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 4.43 (d, J= 4.2H), 4.00 (s, 3H), 3.86 (s, 3H), 3.79-3.77 (m, 2H), 3.59 (s, 3H),3.37 (s, 3H) 67

1-[3-Fluoro-5-(2-hydroxy- ethoxy)-2-pyridyl]-7- methoxy-3-methyl-8-(1-methylpyrazol-4-yl)imidazo- [4,5-c]quinolin-2-one +++ <0.001 MS: 465(M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.89 (s, 1H), 8.46 (s, 1H), 7.95(m, 2H), 7.51 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 5.07 (m, 1H), 4.30(m, 2H), 3.99 (s, 3H), 3.85-3.82 (m, 5H), 3.58 (s, 3H) 68

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-quinolin-2-yl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one + <0.01 MS: 437(M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.905 (s, 1H), 8.801-8.780 (m,1H), 8.254-8.235 (m, 1H), 8.0-032 (m, 1H), 7.949-7.928 (s, 2H),7.850-7.829 (m, 1H), 7.829 (s, 1H), 7.700 (s, 1H), 7.113 (s, 1H), 6.674(s, 1H), 3.965 (s, 3H), 3.671 (s, 3H), 3.596 (s, 3H) 69

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-(1H-pyrrolo[2,3-b]pyridin-6- yl)1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.001 MS: 426 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 8.85 (s, 1H), 8.36 (d, J = 8.1 H), 7.76-7.71 (m, 2H),7.46- 7.41 (m, 2H), 6.75-6.67 (m, 3H), 3.96 (s, 3H), 3.74 (s, 3H), 3.52(s, 3H) 101

1-(3,5-Difluoropyridin-2-yl)- 7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4- yl)-1,3-dihydroimidazo- [4,5-c]quinolin-2-one+++ <0.05 MS: 424 (M + H⁺) 1H NMR (300 MHz, DMSO-d6) ppm = 8.97 (s, 1H),8.84 (s, 1H), 8.57-8.51 (m, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 4.13 (s,3H), 4.04 (s, 3H), 3.61 (s, 3H) 102

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one +++ <0.05 MS: 405 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 8.88 (s, 1H), 8.14-8.11 (s, 2H), 8.04 (s, 1H), 7.54 (s,1H), 4.19 (s, 3H), 4.03-3.99 (d, 6H), 3.56 (s, 3H), 1.56 (s, 3H) 103

1-(3-Fluoro-5-methylpyridin- 4-yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.05 MS: 420 (M + H⁺) 1H NMR (300 MHz,DMSO-d6) ppm = 9.04 (s, 1H), 8.87 (s, 1H), 8.77 (s, 1H), 8.09 (s ,1H),7.68 (s, 1H), 7.61 (s, 1H), 4.40 (s, 3H), 4.04 (s, 3H), 3.62 (s, 3H),2.20 (s, 3H) 104

8-(1-Ethyl-1H-pyrazol-4-yl)- 7-methoxy-1-(3-methoxy-pyridin-4-yl)-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++<0.01 MS: 431 (M + H⁺) 1H NMR (300 MHz, DMSO) ppm = 8.85-8.84 (d, J =4.5, 2H), 8.58-8.57 (d, J = 4.8, 1H), 7.98 (s, 1H), 7.76-7.74 (d, J =5.1, 1H), 7.49 (s, 1H), 7.12-7.10 (d, J = 6.6, 2H), 4.17 (m, 2H), 3.98(s, 3H), 3.57 (s, 3H), 3.36 (s, 3H), 1.39 (m, 3H) 105

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3- methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.001 MS:435 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.89 (s, 1H), 8.45 (s, 1H),7.98 (m, 2H), 7.51 (s, 1H), 7.25 (s, 1H), 6.88 (s, 1H), 4.04 (s, 3H),3.99 (s, 3H), 3.85 (s, 3H), 3.58 (s, 3H) 106

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5- methoxypyridin-2-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.001MS: 449 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.89 (s, 1H), 8.35 (s,1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 6.78 (s, 1H), 3.98 (m,3H), 3.90 (s, 3H), 3.75 (s, 3H), 3.63 (s, 3H), 1.78 (s, 3H) 107

1-(3,5-Difluoropyridin-2-yl)- 7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.001 MS:409 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 11.81 (s, 1H), 8.84 (d, J =2.6 Hz, 1H), 8.68 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.33 (d, J = 0.8Hz, 1H), 6.93 (s, 1H), 3.99 (s, 3H), 3.85 (s, 3H). 108

1-(3,5-Difluoropyridin-2-yl)- 8-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.001 MS:423 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 11.84 (s, 1H), 8.77 (d, J =2.5 Hz, 1H), 8.70 (s, 1H), 8.48 (m, 1H), 7.79 (s, 1H), 7.50 (s, 1H),6.76 (s, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 1.82 (s, 3H). 109

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3-methyl-8-(2H-pyrazol-3-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +++<0.01 MS: 421 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.91 (s, 1H), 8.36(d, J = 2.6 Hz, 1H), 7.93 (m, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.40 (s,1H), 6.54 (s, 1H), 4.01 (s, 3H), 3.97 (s, 3H), 3.57 (s, 3H). 110

1-(3-Fluoro-5-fluoro- methoxypyridin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 453 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.90 (s, 1H),8.65-8.62 (s, 1H), 8.23-8.20 (m, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 7.30(s ,1H), 6.90 (s, 1H), 6.23-6.20 (m, 1H), 6.10-6.01 (s, 1H), 3.99 (s,3H), 3.84 (s, 3H), 3.59 (s, 3H) 111

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-fluoro-5-methoxy-pyridin-2-yl)-7-methoxy-3- methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 449 (M + H⁺) 1H NMR (400 MHz, DMSO)ppm = 8.87 (s, 1H), 8.47 (s, 1H), 7.96 (m, 2H), 7.50 (s, 1H), 7.29 (s,1H), 6.88 (s, 1H), 4.16 (m, 2H), 4.03 (s, 3H), 3.98 (s, 3H), 3.57 (s,3H), 1.36 (m, 3H) 112

1-(3-Ethyl-5-fluoropyridin-4- yl)-7-methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 434 (M + H⁺) 1H NMR (400 MHz, DMSO)ppm = 9.00 (s, 1H), 8.88 (s, 1H), 8.82 (s, 1H), 8.08 (s, 1H), 7.64-7.06(d, J = 16, 2H), 4.08 (s, 3H), 4.03 (s, 3H), 3.62 (s, 3H), 2.57-2.55 (m,2H), 1.03-1.00 (m, 3H) 113

1-(5-Ethoxy-3-fluoropyridin- 2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one+++ <0.001 MS: 449 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.87 (s, 1H),8.43 (s, 1H), 7.94 (m, 2H), 7.50 (s, 1H), 7.24 (s, 1H), 6.87 (s, 1H),4.32 (m, 2 H), 3.98 (s, 3H), 3.84 (s, 3H), 3.57 (s, 3H), 1.44 (m, 3H)114

1-(5-Difluoromethoxy-3- fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 471 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.92 (s, 1H), 8.71(s, 1H), 8.35 (m, 1H), 7.96 (s, 1H), 7.78 (s, 2H), 7.34 (s, 1H), 6.94(s, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 3.32 (s, 3H) 115

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 421 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 11.71 (s, 1H), 8.65(s, 1H), 8.46 (s, 1H), 7.98 (m, 2H), 7.47 (s, 1H), 7.24 (s, 1H), 6.87(s, 1H), 4.04 (s, 3H), 3.98 (s, 3H), 3.85 (s, 3H) 116

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +<0.01 MS: 421 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 11.77 (s, 1H),8.72 (d, J = 16.7 Hz, 2H), 8.64 (s, 1H), 7.98 (s, 1H), 7.47 (s, 1H),7.13 (d, J = 14.7 Hz, 2H), 3.97 (s, 3H), 3.84 (d, J = 8.0 Hz, 6H). 117

1-(3,5-Difluoropyridin-2-yl)- 7-methoxy-3-methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 423 (M + H⁺) 1H NMR (300 MHz, DMSO) ppm = 12.34-12.31 (s, 1H),8.64-8.41 (s, 1H), 8.78 (s, 1H), 8.67-8.59 (m, 1H), 7.52-7.44 (s, 2H),6.74 (s, 1H), 3.91-3.82 (s, 3H), 3.57-3.49 (s, 3H), 2.02-1.87 (m, 3H)118

1-(3,5-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 404 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 12.9 (s, 1H), 8.80(s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.30 (d, J = 0.8 Hz,1H), 3.97 (s, 3H), 3.86 (s, 3H), 3.55 (s, 3H), 1.98 (s, 6H). 119

1-(5-Chloro-3-fluoropyridin- 2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one+++ <0.001 MS: 440 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.91 (s, 1H),8.85 (s, 1H), 8.66 (m, 1H), 8.00 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H),6.96 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 3.59 (s, 3H) 120

7-Methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1-(1H-pyrrolo[3,2-c]pyridin-6- yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.001 MS: 426 (M + H⁺) 1H NMR (400 MHz, DMSO)ppm = 11.97 (s, 1H), 9.00 (s, 1H), 8.84 (s, 1H), 7.78 (s, 2H), 7.71 (d,J = 2.2 Hz, 1H), 7.44 (s, 1H), 6.84 (d, J = 2.9 Hz, 1H), 6.80 (d, 1H),6.73 (s, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.57 (s, 3H) 121

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(1H-pyrazol-3-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++ <0.01MS: 390 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 12.97 (s, 1H), 8.84 (d, J= 40, 1H), 8.07-7.72 (m, 2H), 7.54-6.72 (m, 2H), 6.15 (s, 1H), 4.00-3.92(m, 6H), 3.55 (s, 3H), 1.95 (s, 3H) 122

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3- methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one +++ <0.001 MS:435 (M + H⁺) 1H NMR (300 MHz, DMSO) ppm = 8.84 (s, 1H), 8.31-8.30 (s,1H), 7.81-7.77 (d, J = 12, 1H), 7.50 (s, 2H), 6.76 (s, 1H), 3.99 (s,3H), 3.90 (s, 3H), 3.56 (s, 3H), 1.93 (s, 3H) 123

1-(3-Fluoro-5-piperazin-1-yl- pyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.01 MS: 490 (M + H⁺) 1H NMR (400 MHz,DMSO) ppm = 8.85 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.64(dd, J = 12.7, 2.6 Hz, 1H), 7.48 (s, 1H), 7.28 (s, 1H), 6.89 (s, 1H),3.97 (s, 3H), 3.84 (s, 3H), 3.56 (s, 3H), 3.36 (dd, J = 6.1, 3.8 Hz,4H), 2.88 (t, J = 5.0 Hz, 4H) 124

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3-methyl-8-(2H-pyrazol-3-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one ++<0.05 MS: 421 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 13.0 (d, J = 22.4Hz, 1H), 8.92 (d, J = 16.3 Hz, 1H), 8.68 (dd, J = 15.0, 10.1 Hz, 2H),7.82 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.61-7.45 (m, 1H), 6.73 (t, J =2.1 Hz, 1H), 3.98 (d, J = 7.6 Hz, 3H), 3.84 (d, J = 12.8 Hz, 3H), 3.58(s, 3H). 125

1-(3-Ethyl-5-fluoropyridin-4- yl)-7-methoxy-3-methyl-8-(2H-1,2,3-triazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++<0.001 MS: 420 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 15.25 (s, 1H), 9.00(s, 1H), 8.88 (s, 1H), 8.82 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.62(s, 1H), 4.05 (s, 3H), 3.64 (s, 3H), 2.67-2.51 (m, 2H), 1.03 (m, 3H).126

1-(3-Ethyl-5-fluoropyridin-4- yl)-7-methoxy-3-methyl-8-(1-methyl-1H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 434 (M + H⁺) 1H NMR (400 MHz, DMSO)ppm = 9.00 (s, 1H), 8.87 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 7.92 (s,1H), 7.62 (s, 1H), 4.06 (d, J = 6.0 Hz, 6H), 3.64 (s, 3H), 2.59 (m, 2H),1.03 (t, J = 7.6 Hz, 3H) 127

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3- methyl-8-(2-methyl-2H-1,2,3-triazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++ <0.01MS: 436 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.94 (s, 1H), 8.76 (s,1H), 8.68 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 4.11 (s,3H), 4.02 (s, 3H), 3.86 (s, 3H), 3.59 (s, 3H). 128

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3-methyl-8-(3H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 422 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 15.16 (s, 1H), 8.93 (s, 1H), 8.38 (d, J = 2.6 Hz, 1H),8.23 (s, 1H), 7.96 (dd, J = 11.0, 2.6 Hz, 1H), 7.66 (s, 1H), 7.57 (s,1H), 4.02 (s, 6H), 3.58 (s, 3H). 129

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +<0.001 MS: 435 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 11.8 (s, 1H),8.69-8.62 (m, 3H), 7.79 (s, 1H), 7.46 (s, 1H), 6.95 (s, 1H), 3.90 (s,3H), 3.84 (s, 3H), 3.75 (s, 3H), 1.72 (s, 3H). 130

1-(1-Ethyl-3-methyl-1H- pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.001 MS: 418 (M + H⁺) 1H NMR (400MHz, DMSO) ppm = 8.83 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.49 (s, 1H),7.43 (s, 1H), 7.36 (s, 1H), 4.30-4.20 (m, 2H), 4.00 (s, 3H), 3.88 (s,3H), 3.56 (s, 3H), 1.96 (s, 3H), 1.50 (m, 3H) 131

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3- methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.01MS: 436 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.93 (s, 1H), 8.72 (s,1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.05 (s, 1H), 7.57 (s, 1H), 4.04 (d, J= 9.80 Hz, 6H), 3.84 (s, 3H), 3.59 (s, 3H). 132

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(2-methyl-3H-benzo- imidazol-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.001 MS: 455 (M + H⁺) 1H NMR (400MHz, DMSO) ppm = 12.24 (d, J = 6.5 Hz, 1H), 8.85 (d, J = 2.1 Hz, 1H),8.13 (d, J = 4.9 Hz, 1H), 7.55-7.47 (m, 2H), 7.45-7.36 (m, 1H), 7.26 (d,J = 2.2 Hz, 1H), 7.10 (m, 1H), 3.94- 3.77 (m, 6H), 3.55 (s, 3H), 2.49(s, 3H), 1.94 (s, 3H). 133

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3- methyl-8-(1-methyl-1H-1,2,3-triazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++ <0.01MS: 436 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.92 (s, 1H), 8.43-8.34(m, 2H), 7.96 (dd, J = 11.0, 2.6 Hz, 1H), 7.73 (s, 1H), 7.56 (s, 1H),4.04 (d, J = 13.4 Hz, 9H), 3.58 (s, 3H) 134

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3-methyl-8-(3H-1,2,3-triazol- 4-yl)-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.001 MS: 422 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 15.11 (s, 1H), 8.94 (s, 1H), 8.70 (d, J = 16.3 Hz, 2H),8.25 (s, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 4.03 (s, 3H), 3.85 (s, 3H),3.59 (s, 3H), 2.06 (s, 1H). 135

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-7-methoxy- 3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.001 MS: 432 (M + H⁺) 1H NMR (400MHz, DMSO) ppm = 8.84 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.49 (s, 1H),7.32 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.78 (s, 3H), 3.55(s, 3H), 1.91 (d, J = 15.3 Hz, 6H), 1.40 (t, J = 7.2 Hz, 3H). 136

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3- methyl-8-(2-methyl-3H-benzoimidazol-5-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 485 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 12.23 (s, 1H), 8.93(s, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.60 (s, 1H), 7.56 (s, 1H), 7.50-7.28(m, 2H), 7.07-6.94 (m, 2H), 3.89 (d, J = 2.0 Hz, 6H), 3.59 (s, 3H), 2.49(s, 3H). 137

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-8-(6-methoxypyridin-3-yl)-3- methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one ++ <0.01 MS: 462 (M + H⁺) 1H NMR (400 MHz, DMSO)ppm = 8.95 (s, 1H), 8.65 (d, J = 15.8 Hz, 2H), 8.00 (d, J = 2.4 Hz, 1H),7.65 (dd, J = 8.6, 2.5 Hz, 1H), 7.57 (s, 1H), 6.93 (s, 1H), 6.83 (d, J =8.6 Hz, 1H), 3.87 (d, J = 15.0 Hz, 9H), 3.59 (s, 3H) 138

5-Fluoro-6-[7-methoxy-3- methyl-8-(1-methyl-1H- pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl]-N-methyl- nicotinamid ++ <0.01 MS:462 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 9.08-8.96 (m, 2H), 8.93 (s,1H), 8.55 (dd, J = 9.6, 1.9 Hz, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.30(s, 1H), 6.95 (s, 1H), 4.01 (s, 3H), 3.84 (s, 3H), 3.61 (s, 3H), 2.92(d, J = 4.5 Hz, 3H) 139

6-[8-(1,3-Dimethyl-1H- pyrazol-4-yl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl]-5-fluoro-N-methyl- nicotinamid ++ <0.001 MS: 476 (M + H⁺) 1H NMR (400MHz, DMSO) ppm = 9.02-8.93 (m, 3H), 8.52 (dd, J = 9.5, 1.9 Hz, 1H), 7.80(s, 1H), 7.55 (s, 1H), 6.81 (s, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 3.61(s, 3H), 2.90 (d, J = 4.5 Hz, 3H), 1.76 (s, 3H) 140

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-8-(1-fluoro-methyl-1H-pyrazol-4-yl)-7- methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]-quinolin-2-one +++ <0.001 MS: 453 (M + H⁺) 1H NMR (400 MHz, DMSO-d6)8.91 (s, 1H), 8.74 (d, J = 16.3 Hz, 2H), 8.40 (s, 1H), 7.55 (s, 1H),7.40- 7.35 (m, 1H), 7.19 (s, 1H), 6.22 (s, 1H), 6.09 (s, 1H), 4.00 (s,3H), 3.85 (s, 3H), 3.59 (s, 3H). 141

1-(3-Fluoro-1-methyl-1H- pyrazol-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.01 MS: 408 (M + H⁺) 1H NMR (400 MHz,DMSO) ppm = 8.82 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.60(s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.86(s, 3H), 3.53 (s, 3H). 142

8-(1-Ethyl-3-methyl-1H- pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7- methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]quinolin-2-one ++ <0.001 MS: 463 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm =8.92 (s, 1H), 8.71 (d, J = 11.5 Hz, 2H), 7.86 (s, 1H), 7.54 (s, 1H),7.01 (s, 1H), 4.07 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.61 (s, 3H),1.78 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 143

8-(1-Difluoromethyl-1H- pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7- methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]quinolin-2-one ++ <0.001 MS: 471 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm= 8.93 (s, 1H), 8.72 (d, J = 14.3 Hz, 2H), 8.47 (s, 1H), 7.83 (t, J =58.9 Hz, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.21 (s, 1H), 4.01 (s, 3H),3.85 (s, 3H), 3.59 (s, 3H). 144

1-(3-Fluoro-5-methoxy- pyridin-2-yl)-7-methoxy-3- methyl-8-(2-methyl-3H-benzoimidazol-5-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.001MS: 485 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 12.21 (s, 1H), 8.93 (s,1H), 8.35 (d, J = 2.6 Hz, 1H), 7.95- 7.81 (m, 1H), 7.55 (s, 1H), 7.38(d, J = 21.1 Hz, 2H), 7.01 (d, J = 32.5 Hz, 1H), 6.72 (s, 1H), 3.93 (d,J = 27.1 Hz, 6H), 3.58 (s, 3H), 2.48 (d, J = 1.9 Hz, 3H). 145

1-[3-Fluoro-5-(trideuterio- methoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1- methylpyrazol-4-yl)imidazo- [4,5-c]quinolin-2-one++ <0.001 MS: 438 (M + H⁺) 1H NMR (300 MHz, DMSO-d6) ppm = 8.89 (s, 1H),8.75 (d, J = 12.1 Hz, 2H), 7.99 (s, 1H), 7.52 (s, 1H), 7.20-7.11 (m,2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.31 (s, 3H). 146

1-(3-Difluoromethoxy-5- fluoropyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 471 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 9.06 (s, 1H),8.93 (d, J = 3.7 Hz, 2H), 8.02 (s, 1H), 7.58 (s, 0H), 7.54 (s, 1H), 7.42(d, J = 1.6 Hz, 0H), 7.27- 7.20 (m, 1H), 7.16 (s, 1H), 4.01 (s, 3H),3.86 (s, 3H), 3.62 (s, 3H) 147

1-(3-Difluoromethoxy-5- fluoropyridin-4-yl)-8-(1,3-dimethyl-1H-pyrazol-4-yl)-7- methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]- quinolin-2-one +++ <0.001 MS: 485 (M + H⁺) 1H NMR(400 MHz, DMSO-d6) ppm = 9.03 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 7.84(s, 1H), 7.56 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.21 (s,0H), 7.00 (s, 1H), 3.95 (s, 3H), 3.78 (s, 3H), 3.62 (s, 3H), 1.75 (s,3H) 148

1-(3-Fluoro-5-fluoro- methoxypyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one +++<0.001 MS: 453 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 9.04-8.79 (m,3H), 8.00 (s, 1H), 7.54 (s, 1H), 7.18 (d, J = 21.6 Hz, 2H). 5.95 (m,2H), 4.01 (s, 3H), 3.86 (s, 3H), 3.61 (s, 3H). 149

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5-fluoro-methoxypyridin-4-yl)-7- methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]-quinolin-2-one +++ <0.001 MS: 467 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm= 9.00-8.75 (m, 3H), 7.83 (s, 1H), 7.55 (s, 1H), 6.99 (s, 1H), 5.93 (m,2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.61 (s, 3H), 1.74 (s, 3H) 150

8-(1,3-Dimethylpyrazol-4- yl)-1-[3-fluoro-5-(trideuterio-methoxy)-4-pyridyl]-7- methoxy-3-methyl-imidazo- [4,5-c]quinolin-2-one+++ <0.001 MS: 452 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.92 (s,1H), 8.70 (d, J = 9.5 Hz, 2H), 7.83 (s, 1H), 7.54 (s, 1H), 7.00 (s, 1H),3.94 (s, 3H), 3.78 (s, 3H), 3.60 (s, 3H), 1.75 (s, 3H). 151

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(4-methyl-1H-pyrazol-3-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one +++<0.05 MS: 404 (M + H⁺) 152

1-(3-Fluoro-5-methoxy- pyridin-4-yl)-7-methoxy-3- methyl-8-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one+++ <0.001 MS: 486 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 12.87- 12.50(m, 1H), 8.99 (s, 1H), 8.65 (d, J = 14.3 Hz, 2H), 8.11 (d, J = 23.8 Hz,1H), 7.78 (d, J = 12.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.06-6.98 (d,J = 20 Hz, 1H), 3.93 (s, 3H), 3.89 (d, J = 6.8 Hz, 3H), 3.63 (s, 3H),2.55 (d, J = 14.3 Hz, 3H). 153

8-(3H-Benzimidazol-5-yl)-1- (3-fluoro-5-methoxypyridin-2-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++<0.01 MS: 471 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 12.47 (s, 1H),8.93 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.24 (s, 1H), 7.88 (d, J = 10.9Hz, 1H), 7.56 (s, 3H), 7.19- 7.00 (m, 1H), 6.75 (s, 1H), 3.90 (s, 3H),3.59 (s, 3H), 3.31 (s, 3H). 154

1-(1,3-Dimethyl-1H-pyrazol- 4-yl)-7-methoxy-3-methyl-8-(2-methyl-1H-imidazo[4,5- b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one + <0.001 MS: 455 (M + H⁺) 1H NMR (400 MHz,DMSO-d6) ppm = 8.91 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H),7.59 (s, 1H), 7.29 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.58 (s, 3H),2.56 (s, 3H), 1.97 (s, 3H). 155

1-[3-Fluoro-5-(trideuterio- methoxy)-2-pyridyl]-7-methoxy-3-methyl-8-(1- methylpyrazol-4-yl)imidazo- [4,5-c]quinolin-2-one+++ <0.001 MS: 438 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.89 (s, 1H),8.47 (s, 1H), 7.98 (m, 2H), 7.52 (s, 1H), 7.25 (s, 1H), 6.88 (s, 1H),3.99 (s, 3H), 3.85 (s, 3H), 3.59 (s, 3H) 156

1-(3-Ethylpyridin-4-yl)-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c] quinolin-2-one ++<0.001 MS: 415 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.93 (s, 1H),8.89 (s, 1H), 8.78 (d, 1H), 7.95 (s, 1H), 7.65 (d, 1H), 7.50 (s, 1H),6.97 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H), 3.83 (s, 3H), 3.59 (s, 3H),2.50 (m, 2H), 0.99-0.95 (m, 3H) 157

8-(1-Ethyl-1H-pyrazol-4-yl)- 1-(3-ethylpyridin-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c] quinolin-2-one +++ <0.01 MS:429 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.88 (s, 1H), 8.14-8.11 (s,2H), 8.04 (s, 1H), 7.54 (s, 1H), 4.19 (s, 3H), 4.03-3.99 (d, 6H), 3.56(s, 3H), 1.56 (s, 3H) 158

1-(3-Fluoropyridin-2-yl)-7- methoxy-3-methyl-8-(2-methyl-2H-1,2,3-triazol-4- yl)-1,3-dihydroimidazo- [4,5-c]quinolin-2-one++ <0.5 MS: 406 (M + H⁺) 1H NMR (400 MHz, DMSO-d6) ppm = 8.96 (s, 1H),8.68 (s, 1H), 8.27-8.23 (m, 1H), 8.07 (s, 1H), 7.96-7.92 (m, 1H), 7.57(s, 1H), 7.51 (s, 1H), 4.10 (s, 3H), 4.02 (s, 3H), 3.59 (s, 3H) 159

1-(3-Fluoro-1-methyl-1H- pyrazol-4-yl)-7-methoxy-8-(6-methoxypyridin-3-yl)-3- methyl-1,3-dihydroimidazo-[4,5-c]quinolin-2-one + <0.01 MS: 435 (M + H⁺) 1H NMR (400 MHz, DMSO-d6)ppm = 8.90 (s, 1H), 8.19 (dd, J = 2.4, 0.8 Hz, 1H), 7.89 (d, J = 2.4 Hz,1H), 7.76 (dd, J = 8.6, 2.5 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H),6.92-6.84 (m, 1H), 3.89 (d, J = 8.2 Hz, 6H), 3.82 (d, J = 1.1 Hz, 3H),3.55 (s, 3H). 200

1-(3-Cyclopropylpyridin-4- yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c] quinolin-2-one ++<0.05 MS: 427 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.87 (s, 1H), 8.73(d, J = 5.1, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.64 (d, J = 5.1 Hz, 1H),7.49 (s, 1H), 6.98-6.92 (m, 2H), 3.97 (s, 3H), 3.82 (s, 3H), 3.58 (s,3H), 1.59 (m, 1H), 0.91 (m, 1H), 0.82-0.73 (m, 1H), 0.62-0.49 (m, 2H).201

1-(3-Fluoro-5-methyl- sulfonylmethoxypyridin-2-yl)-7-methoxy-3-methyl-8- (1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]- quinolin-2-one +++ <0.001 MS: 514 (M + H⁺) 1HNMR (400 MHz, DMSO) ppm = 8.91 (s, 1H), 8.66 (s, 1H), 8.28 (m, 1H), 7.89(s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.95 (s, 1H), 5.70 (s, 2H), 4.02(s, 3H), 4.00 (s, 3H), 3.59 (s, 3H), 3.21 (s, 3H) 202

1-(3-Cyclopropyl-5-fluoro- pyridin-4-yl)-7-methoxy-3-methyl-8-(1-methyl-1H- pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2- one ++ <0.001 MS: 445 (M + H⁺) 1H NMR (400MHz, DMSO) ppm = 8.91 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 7.98 (s, 1H),7.52 (s, 1H), 7.08-6.99 (m, 2H), 3.98 (s, 3H), 3.83 (s, 3H), 3.60 (s,3H), 1.71-1.61 (m, 1H), 1.04-0.95 (m, 1H), 0.87 (m, 1H), 0.37-0.62 (m,2H). 203

8-(1,3-Dimethyl-1H-pyrazol- 4-yl)-1-(3-fluoro-5-methyl-sulfonylmethoxypyridin-2- yl)-7-methoxy-3-methyl-1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++ <0.001 MS: 528 (M + H⁺) 1H NMR(400 MHz, DMSO) ppm = 8.92 (s, 1H), 8.56 (s, 1H), 8.22 (m, 1H), 7.75 (s,1H), 7.53 (s, 1H), 6.83 (s, 1H), 5.64 (s, 2H), 3.92 (s, 3H), 3.76 (s,3H), 3.58 (s, 3H), 3.17 (s, 3H), 1.826 (s, 3H) 204

1-(5-Allyloxy-3-fluoropyridin- 2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)- 1,3-dihydroimidazo[4,5-c]- quinolin-2-one ++<0.001 MS: 461 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.87 (s, 1H), 8.46(d, J = 2.6 Hz, 1H), 8.01-7.93 (m, 2H), 7.50 (s, 1H), 7.24 (d, J = 0.8Hz, 1H), 6.87 (s, 1H), 6.11 (ddt, J = 17.2, 10.6, 5.3 Hz, 1H), 5.51 (dq,J = 17.3, 1.6 Hz, 1H), 5.38 (dq, J = 10.5, 1.4 Hz, 1H), 4.88 205

1-[5-(Azetidin-3-yloxy)-3- fluoropyridin-2-yl]-7- methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]- quinolin-2-one ++<0.001 MS: 476 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.87 (s, 1H), 8.40(s, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 6.89(s, 1H), 5.28 (m, 1H), 3.98 (s, 3H), 3.85 (s, 2H), 3.84 (s, 3H), 3.62(s, 2H), 3.57 (s, 3H) 206

1-[3-Fluoro-5-(2-methyl- amino-ethoxy)-pyridin-2-yl]-7-methoxy-3-methyl-8-(1- methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c] quinolin-2-one ++ <0.01 MS: 478 (M + H⁺) 1H NMR(400 MHz, DMSO-d6) ppm = 8.87 (s, 1H), 8.44 (d, J = 2.6 Hz, 1H), 7.97(d, J = 13.0 Hz, 2H), 7.50 (s, 1H), 7.26 (d, J = 0.8 Hz, 1H), 6.89 (s,1H), 4.36-4.27 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.57 (s, 3H),2.97-2.89 (m, 2H), 2.37 (s, 3H). 207

1-[3-Fluoro-5-(1-methyl- azetidin-3-ylmethoxy)-pyridin-2-yl]-7-methoxy-3- methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2- one ++ <0.01 MS:505 (M + H⁺) 1H NMR (400 MHz, DMSO) ppm = 8.87 (s, 1H), 8.45 (d, J = 2.5Hz, 1H), 7.98 (d, J = 12.0 Hz, 2H), 7.50 (s, 1H), 7.25 (s, 1H), 6.86 (s,1H), 4.42-4.35 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.57 (s, 3H), 3.35(s, 2H), 3.02 (t, J = 6.20 Hz, 2H), 2.84 (m, 1H), 2.22 (s, 3H). 208

8-[1-(Azetidin-3-yl)-1H- pyrazol-4-yl]-1-(3-fluoro-5-methoxypyridin-4-yl)-7- methoxy-3-methyl- 1H,2H,3H-imidazo[4,5-c]-quinolin-2-one + <0.01 MS: 476 (M + H⁺) H NMR (400 MHz, DMSO-d6) ppm =8.90 (s, 1H), 8.78 (s, 1H), 8.74 (s, 1H), 8.11 (s, 1H), 7.53 (s, 1H),7.28 (s, 1H), 7.17 (s, 1H), 5.21 (m, 1H), 4.00 (s, 3H), 3.96-3.84 (m,5H), 3.71 (t, J = 7.9 Hz, 2H), 3.59 (s, 3H) +++: 0.2 μM or less ++: >0.2μM to 1 μM +: >1 μM to 2 μM

Compounds according to the invention not only have very good inhibitionof ATM kinase, they are also in addition very selective towards otherkinases, such as, for example, mTOR, PIK3 alpha, PI3K beta, PI3K deltaand PI3K gamma, which is confirmed with reference to the experimentaldata shown in Table 3 below:

TABLE 3 IC₅₀ IC50 IC50 IC50 IC50 IC50 (ATM) (PI3Kalpha) (PI3Kbeta)(PI3Kdelta) (PI3Kgamma) (mTOR) Ex. [μM] [μM] [μM] [μM] [μM] [μM] 1<0.01 >30 >30 >30 >30 >30 2 <0.001 >30 >30 >30 >30 >5 3<0.001 >30 >30 >30 >30 >5 4 <0.001 >5 >30 >10 >30 >30 5<0.001 >30 >30 >30 >30 >30 6 <0.001 >30 >30 >30 >30 >30 7<0.001 >30 >30 >30 >30 >30 8 <0.001 >30 >30 >30 >30 >5 9<0.001 >30 >30 >30 >30 >10 10 <0.001 >30 >30 >30 >30 >30 11<0.001 >30 >30 >30 >30 >30 12 <0.001 >30 >30 >30 >30 >30 13<0.001 >5 >30 >10 >30 >10 14 <0.001 >30 >30 >30 >30 >30 15<0.001 >30 >30 >30 >30 >30 16 <0.001 >30 >30 >30 >30 >30 17<0.01 >30 >30 >30 >30 >10 18 <0.001 >10 >30 >30 >5 >5 19<0.01 >30 >30 >30 >5 20 <0.001 >30 >30 >30 >30 >30 21<0.001 >20 >30 >30 >300 >5 22 <0.001 >30 >30 >30 >30 23<0.01 >20 >30 >30 >30 >20 24 <0.001 >30 >30 >30 >30 >30 25<0.001 >30 >30 >30 >30 >30 26 <0.001 >30 >30 >30 >30 27<0.001 >30 >30 >30 >30 >30 28 <0.01 >30 >30 >30 >30 >30 29<0.01 >30 >30 >30 >30 >30 30 <0.01 >30 >30 >30 >30 >30 31<0.01 >30 >30 >30 >30 >30 32 <0.01 >30 >30 >30 >10 33<0.001 >30 >30 >30 >30 >30 34 <0.01 >30 >30 >30 >30 >30 35<0.01 >30 >30 >30 >30 >30 36 <0.001 >30 >30 >30 >30 >30 37<0.01 >30 >30 >30 >30 >10 38 <0.001 >30 >30 >30 >30 >30 39<0.001 >30 >30 >30 >30 40 <0.01 >30 >30 >30 >30 >30 41<0.01 >30 >30 >30 >30 >10 43 <0.001 >30 >30 >30 >30 >30 44<0.01 >30 >30 >30 >30 >30 45 <0.05 >30 >30 >30 >30 >30 46<0.05 >30 >30 >30 >30 >30 47 <0.01 >30 >30 >30 >30 >30 49<0.01 >30 >30 >30 >30 >30 51 <0.01 >30 >30 >30 >30 >30 53<0.01 >30 >30 >30 >30 >30 54 <0.01 >30 >30 >30 >30 55<0.01 >30 >30 >30 >30 >30 57 <0.05 >30 >30 >30 >30 >30 58<0.01 >30 >30 >30 >30 >30 59 <0.01 >30 >30 >30 >30 >30 60<0.01 >30 >30 >30 >30 >30 61 <0.01 >30 >30 >30 62 <0.01 >30 >30 >30 >30>30

For the other compound examples, the following advantageous values havealready been determined:

With respect to mTOR, the following compound examples have an IC50 (ATM)which is at least 2000 times higher (compared with IC50 (mTOR)), wherethe ratio IC50 (ATM):IC50(mTOR) even exceeds 100,000 in the case of somecompound examples: 114, 118, 120, 121, 122, 125, 126, 136, 138, 140,141, 145, 147, 149, 157, 159, 201.

With respect to PI3Kalpha, the following compound examples have an IC50(ATM) which is at least 2000 times higher: 66, 67, 105, 108, 110, 114,117, 120, 122, 123, 125, 126, 155, 201, 205.

With respect to PI3Kbeta, the following compound examples have an IC50(ATM) which is at least 2000 times higher (compared with IC50(PI3Kbeta)), where the ratio IC50 (ATM):IC50(PI3Kbeta) exceeds 10,000 inthe case of some compound examples: 108, 118, 125, 136, 137, 140, 145,149, 159, 201.

With respect to PI3Kdelta, the following compound examples have an IC50(ATM) which is at least 2000 times higher: 66, 67, 105, 108, 110, 114,117, 120, 122, 123, 125, 126, 145, 155, 201, 205.

With respect to PI3Kgamma, the following compound examples have an IC50(ATM) which is at least 2000 times higher: 66, 67, 105, 108, 110, 114,117, 120, 122, 123, 125, 126, 136, 145, 149, 155, 201, 205.

Example 15

Further compounds which can be prepared correspondingly or analogouslyto EXAMPLES 1 to 12 are shown in Table 4 below.

TABLE 4 300

1-(3-Fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-8-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one 301

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3-methyl-8-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one 302

1-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one 303

1-[3-Fluoro-5-(trifluoromethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one 304

1-[3-Fluoro-5-(trifluoromethoxy)-4-pyridyl]-7-methoxy-3-methyl-8-(1,3-dimethylpyrazol-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one 400

1-(3-Fluoro-5-methylsulfonyl-pyridin-2-yl)-7-methoxy-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H,2H,3H-imidazo[4,5-c]quinolin-2-one 401

8-[1-(Azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl]-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methyl-1H,2H,3H-imidazo[4,5-c]quinolin-2-one

Example A: Injection Vials

A solution of 100 g of active compound according to the invention and 5g of disodium hydrogenphosphate in 3 l of bidistilled water is adjustedto pH 6.8 using 2 N hydrochloric acid, sterile-filtered, transferredinto injection vials, lyophilised under sterile conditions and sealedunder sterile conditions. Each injection vial contains 5 mg of activecompound according to the invention.

Example B: Suppositories

A mixture of 20 g of active compound according to the invention with 100g of soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activecompound according to the invention.

Example C: Solution

A solution is prepared from 1 g of active compound according to theinvention, 9.38 g of NaH₂PO₄*2 H₂O, 28.48 g of Na₂HPO₄*12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of active compound according to the invention are mixed with 99.5g of Vaseline under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active compound according to the invention, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active compound according to theinvention.

Example F: Dragees

Tablets are pressed analogously to Example E and then coated in aconventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G: Capsules

2 kg of active compound according to the invention are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of active compound according to the invention.

Example H: Ampoules

A solution of 1 kg of active compound according to the invention in 60 lof bidistilled water is sterile-filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound according tothe invention.

Example I: Inhalation Spray

14 g of active compound according to the invention are dissolved in 10 lof isotonic NaCl solution, and the solution is transferred into standardcommercial spray vessels with pump mechanism. The solution can besprayed into the mouth or nose. One spray shot (approx. 0.1 ml)corresponds to a dose of approx. 0.14 mg.

The invention claimed is:
 1. A compound of formula (IV) or apharmaceutically acceptable salt, solvate, tautomer or stereoisomerthereof,

wherein Het¹ denotes pyrazolyl, which is unsubstituted or mono-, di- ortrisubstituted, independently of one another, by Hal or A, A in eachcase independently denotes unbranched or branched alkyl having 1, 2, 3,4, 5, or 6 C atoms, in which, independently of one another, 1, 2, 3, 4,or 5 H atoms are optionally replaced by Hal, Hal denotes F, Cl, Br or I,and HET is 3-difluoromethoxy-5-fluoropyridin-4-yl,3-fluoro-5-methoxypyridin-4-yl, 3-fluoro-5-fluoromethoxypyridin-4-yl, or3-fluoro-5-(trideuteriomethoxy)pyridin-4-yl.
 2. The compound accordingto claim 1, wherein Het¹ is 1H-pyrazol-4-yl, 2H-pyrazol-3-yl,1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-fluoro-methyl-1H-pyrazol-4-yl, 1-difluoromethyl-1H-pyrazol-4-yl,1,3-dimethyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-ethyl-3-methyl-1H-pyrazolyl, or 3-fluoro-1-methyl-1H-pyrazol-4-yl. 3.The compound according to claim 1, or a pharmaceutically acceptable saltthereof.
 4. The compound according to claim 1, which contains one ormore deuterium atoms.
 5. A compounds, which is one of the followingcompounds

or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomerthereof.
 6. The compound according to claim 5, which is the followingcompound or a pharmaceutically acceptable salt of the following compound


7. The compound according to claim 5, which is the following compound ora pharmaceutically acceptable salt of the following compound


8. The compound according to claim 5, which is the following compound ora pharmaceutically acceptable salt of the following compound


9. The compound according to claim 5, which is the following compound


10. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


11. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


12. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


13. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


14. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


15. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


16. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


17. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


18. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


19. The compound according to claim 5, which is the following compoundor a pharmaceutically acceptable salt of the following compound


20. The compound according to claim 5, or a pharmaceutically acceptablesalt thereof.
 21. A pharmaceutically acceptable salt of the followingcompound according to claim 5, which is the following compound